Abstract
Despite the substantial global health and economic burden of apicomplexan parasites in humans and livestock, treatment options remain limited. Natural products have long played an important role in combating these diseases, offering diverse chemical structures and bioactive compounds. This review summarises past and present natural-product-based therapies for six economically significant apicomplexans and explores the potential of revisiting natural products as a source of next-generation treatments.
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Introduction
The phylum Apicomplexa represents a diverse group of intracellular, single-celled parasites, comprising more than 6000 known species1. These parasites are primarily distinguished by the presence of an apical complex, a specialised structure containing secretory organelles that facilitate host cell invasion2,3. Depending on the species, apicomplexan parasites can infect a wide range of vertebrate and invertebrate hosts, often involving complex, multi-host lifecycles that span various cell types and tissues4. Some of these parasites are prevalent globally and pose significant health and economic challenges as the causative agents of diseases in both humans and animals.
Current control and treatment options for apicomplexan parasites are limited. To date, there are only a small number of effective and commercially accessible vaccines for disease prevention5. The extensive use of pesticides to block transmission has led to widespread pesticide resistance across endemic areas6,7,8,9. Additionally, many of the clinically recommended and frontline drugs for treating apicomplexan parasites are hindered by their low efficacy10,11,12,13,14, toxic side effects15, and the emergence of parasite resistance mechanisms16,17,18,19,20,21,22. Therefore, there is an urgent need for new therapeutic options to combat the burden of apicomplexan parasites on public health and the global economy.
Natural products from plants, fungi, and bacteria have historically provided a rich source of new therapeutic agents, contributing to 66% of all small-molecule anti-infectives and 71% of approved cancer drugs between 1981 and 201923. Several have had a profound impact on modern medicine, including the current frontline anti-malarial agent, artemisinin, whose discovery by Professor Youyou Tu earned her the 2015 Nobel Prize in Physiology or Medicine24,25. With >400,000 unique natural compounds curated to date26, and many more still to uncover from promising screens encompassing a diverse range of plants, fungi, bacteria, and even marine organisms27,28,29,30, there remains significant scope for natural products to be revisited as a source of next-generation drugs against apicomplexan parasites. This review summarises the most prominent natural products and their derivatives that have been clinically used to treat six apicomplexan genera that impose a significant global health and economic burden, these being Plasmodium, Cryptosporidium, Toxoplasma, Eimeria, Babesia and Theileria. Furthermore, we discuss the potential of natural products as future therapeutic agents given the deficiencies of current control strategies and the difficulty of developing an affordable and effective novel drug for use in all environments.
Apicomplexan parasites of significant global health and economic burden
Several parasites within the Apicomplexa phylum are responsible for severe diseases affecting either or both humans and animals, however, this review will focus on six key pathogens of notable economic significance that have approved drug treatments available (Fig. 1). While other apicomplexans also cause economically important levels of disease in livestock, such as Neospora caninum, Sarcocystis spp., Isospora spp., and Besnoitia besnoiti, specific treatments for these parasites are not typically available and treatments described in the literature are generally off-label uses of anti-parasitic drugs indicated for the treatment of other parasites.
The Apicomplexa phylum comprises over 6000 species, capable of infecting a broad range of hosts. These six genera and species are the focus for this review as they have a disproportionately large health and economic impact on the represented hosts compared with other apicomplexans and/or have a more developed history of clinical drug use in humans and livestock.
Malaria, caused by Plasmodium spp., remains one of the most debilitating apicomplexan diseases in humans, affecting over 200 million people each year, leading to more than half a million fatalities31. Approximately 95% of all deaths occur in sub-Saharan Africa, of which around 80% are among children under the age of five31. Of the five human-infecting Plasmodium spp., P. falciparum stands as the deadliest and most prevalent in the African region, with P. vivax and P. knowlesi progressively emerging as substantial threats in the Americas and Southeast Asia31.
Cryptosporidiosis, caused by Cryptosporidium spp., is a leading cause of severe diarrhoeal disease in children, responsible for over 200,000 deaths annually in South Asia and sub-Saharan Africa alone32. These parasites are transmitted through the ingestion of infective oocysts that are highly resistant in the environment to chlorine, among other conventional disinfectants, rendering them a major threat in waterborne outbreaks33. Furthermore, up to one third of the global population is chronically infected with Toxoplasma gondii, the causative agent of toxoplasmosis34. Although considered asymptomatic in healthy individuals, T. gondii can cause severe complications in immunocompromised patients and pregnant women, including encephalitis, ocular damage, congenital defects and miscarriage35,36,37. In addition, T. gondii infections have been associated with an increased risk of chronic physical and mental health problems such as heart disease and schizophrenia38,39,40,41, suggesting that the broader health impacts of this widespread parasite could be much greater than indicated by acute infection.
The economic impact of apicomplexan diseases extends beyond human health to livestock, with several animals raised for food production facing constant threats from parasitic infection. Toxoplasmosis, for example, has long been associated with increased abortion rates in sheep42,43,44, although estimating its full economic impact has been challenging due to the complex factors influencing neonatal mortality45. Coccidiosis, caused by Eimeria species, and cryptosporidiosis, are well-known gastrointestinal illnesses of cattle, sheep, goats, and poultry, leading to diarrhoea, reduced growth rates, and, in severe cases, death45,46. Recent estimates indicate that coccidiosis alone costs the commercial poultry industry more than £10 billion annually47, while cryptosporidiosis can incur losses of up to €60 per affected calf on dairy farms in Europe, where approximately 11 million calves are raised for milk production each year48. Additionally, babesiosis and theileriosis, caused by Babesia and Theileria species, respectively, also contribute to significant livestock losses in cattle, costing industries over US $300 million in annual losses alongside other tick-borne diseases due to decreased dairy and meat production49. Many of these apicomplexan diseases disproportionately affect populations in low- and middle-income regions, further imposing a heavy financial burden on individuals, families and health systems50,51.
Current therapeutic avenues for apicomplexan parasites
The control and eradication of apicomplexan pathogens have proven challenging, partly due to the complex, multi-host lifecycles of these parasites and the lack of readily available, and economically accessible resources in endemic areas. Currently, the only commercially approved vaccines for apicomplexans in humans are two recombinant subunit vaccines for malaria: RTS,S/AS01 and R21/Matrix-M52,53. For use in livestock, live attenuated vaccines are available for some apicomplexans in endemic areas, such as Toxovax® for T. gondii in sheep54, the Combavac 3 in 1 vaccine for Babesia in cattle55, and several commercial Eimeria vaccines56. Additionally, the recombinant antigen vaccine, Bovilis Cryptium, has also received United Kingdom Veterinary Medicines Directorate (VMD) approval in the last year for use in protecting newborn calves against C. parvum in pregnant cows57. However, concerns remain regarding the long-term efficacy of malaria vaccines52,53, and many livestock vaccines are geographically restricted for commercial use, leaving a significant proportion of endemic countries unprotected. For example, the Combavac 3 in 1 vaccine is currently only approved for use in Australia56, while Toxovax® is available in New Zealand and some parts of Europe54. Moreover, logistical challenges such as the short shelf-life of Toxovax® (less than 10 days) further highlight the difficulties of vaccine development for apicomplexans.
For vector-borne parasites like Plasmodium, Babesia and Theileria, chemical pesticides such as organophosphates and pyrethroids have been widely used to curb transmission, though their effectiveness is increasingly compromised by the emergence of insecticide and acaricide resistance6,7,8,9. For parasites that are spread through environmental contamination, such as T. gondii, Cryptosporidium, and Eimeria, meticulous hygiene and biosecurity measures are among the most important methods for disease prevention34,58,59,60.
Clinically approved drug treatments are available for disease management in both humans and livestock, however, treatment options remain limited for the majority of apicomplexans (Table 1). The World Health Organisation (WHO) currently recommends artemisinin-based combination therapies (ACTs) as the gold standard for malaria treatment61. ACTs combine a short-acting artemisinin-based anti-malarial with a longer-acting partner drug, such as lumefantrine, amodiaquine and mefloquine, to minimise the selective pressure for resistance development61,62,63,64. For the treatment of cryptosporidiosis, nitazoxanide is currently the only approved drug for human use, however, it is ineffective in those with weakened immune systems, who are at a greater risk of fatal disease10,11.
For human infections with toxoplasmosis, a combination of pyrimethamine and sulfadiazine is the most widely used therapy15. However, this combination is often poorly tolerated, with one study reporting adverse side effects in up to 60% of toxoplasma encephalitis patients, of which 45% required treatment discontinuation15. Unfortunately, few alternatives are available for those who cannot tolerate standard treatment. Repurposed antibiotics such as spiramycin, and to a lesser extent clindamycin and azithromycin, have been used or trialled as alternatives to treat active infections, but there is limited evidence supporting their efficacy12,13,14,65.
In veterinary medicine, drug treatments have demonstrated varying effectiveness against apicomplexan parasites. For cryptosporidiosis in calves, halofuginone and paromomycin are the two primary treatments used to reduce oocyst shedding and disease severity66,67,68,69, whereas imidocarb is the drug of choice for bovine babesiosis70,71, and buparvaquone for bovine theileriosis70,72. Coccidiosis in chickens is managed with a range of natural polyether ionophores and synthetic drugs, with the choice of drug largely based on where in the lifecycle the drug is most effective and previous anti-parasitic drug use for the flock. Most drug use for coccidiosis in chickens is for prevention, including the ionophores, diclazuril and nicarbazin, whereas amprolium and antifolates are primarily used for treatment70. Many of these anti-coccidials are also recommended for clinical treatment of coccidiosis in pigs caused by the closely related Isospora suis73,74. In the case of toxoplasmosis, there are currently no anti-toxoplasma treatments registered for use in livestock75. Many existing drugs, including spiramycin, pyrimethamine, sulfonamides, polyether ionophores, and other anti-coccidials, have been trialled against T. gondii in sheep and the closely related N. caninum in cattle, however, no feasible treatment regimen has emerged for clinical use against ovine toxoplasmosis or bovine neosporosis76.
Historical importance of natural products in the treatment of apicomplexans
Many pharmaceuticals on the market today have been developed from natural products or their derivatives77. Among the current most widely used drugs in clinical settings for apicomplexan infections in humans and livestock (Fig. 2)61,70,78, around 39% are natural products or their semi-synthetic derivatives, and a further 22% are synthetic compounds inspired by naturally occurring pharmacophores. Tables 2 and 3 provide a summary of these natural products and showcase the range of derivatives that have arisen from natural product scaffolds, either made synthetically, or semi-synthetically by chemical modification of existing natural products. In the following, we summarise the naturally derived drugs that have either historically been used, or are currently in use, to treat apicomplexan infections.
Around 39% are natural products or chemically modified derivatives (semi-synthetic), and a further 22% are synthetic compounds inspired by natural pharmacophores. Clinical resistance has emerged to the majority of these drugs, leaving few alternatives with strong therapeutic potential available.
Quinine
Quinine, first isolated in 1820 from the bark of the Peruvian Cinchona tree, had been used medicinally to treat a variety of fevers in South America for centuries before introduction to Europe in the 1600s where it was found by analogy to be useful in the treatment of intermittent fevers associated with malaria62. Quinine remained the frontline anti-malarial until the 1940s, by which point access to more effective synthetic drugs was facilitated by the US Army’s malaria drug discovery programs62. The most important of these was chloroquine, a quinoline-containing compound first described in 193879,80 that became heavily used in the 1940s81, and is still recommended in areas with chloroquine-susceptible infections61. Several other synthetic derivatives discovered after chloroquine, such as amodiaquine, mefloquine, piperaquine and pyronaridine, are incorporated as partner drugs in ACTs81,82,83,84. Although the exact mechanism of action for many quinoline-based drugs remains an active area of research, it is thought that in part, their efficacy is via inhibiting the polymerisation of toxic haem released during the parasite’s digestion of haemoglobin85,86,87.
Artemisinin
Artemisinin was discovered in 1972 as the active anti-malarial component of Artemisia annua, a herbal plant traditionally used to treat fevers and chills during malaria infections88. Unlike previous anti-malarials, artemisinin was shown to rapidly clear malaria parasites within hours of administration, however, its short half-life has limited its use as an oral monotherapy89,90. Subsequent modifications to artemisinin led to the development of analogues with enhanced metabolic stability and efficacy, including dihydroartemisinin, artemether, and artesunate, which are now clinically used in ACTs for uncomplicated malaria and as intravenous monotherapies for severe malaria61,91. The unique structure of the artemisinins offers a distinct mechanism of action against malaria parasites, differentiating them from previous quinine-derived and synthetic drugs. It is now widely accepted that the bioactivation of artemisinin from iron-mediated cleavage of the endoperoxide bridge generates free oxygen radicals that promiscuously alkylate essential proteins and biomolecules, ultimately leading to parasite death92,93.
Spiramycin
Spiramycin is a macrolide antibiotic originally isolated from Streptomyces ambofaciens in 195494. In apicomplexan parasites, spiramycin is thought to inhibit protein synthesis in the bacterial-like ribosomes of an essential plastid organelle called the apicoplast95. One of the first studies to demonstrate the anti-Toxoplasma potential of spiramycin in humans was conducted in 1961 for ocular toxoplasmosis96, though its primary clinical use has since been for preventing congenital toxoplasmosis, to avoid potential teratogenic risks associated with the standard pyrimethamine-sulfadiazine combination therapy97. Studies in pregnant women have shown that spiramycin can reduce congenital transmission of T. gondii to the foetus, potentially by accumulating in the placenta98,99,100. However, since transfer of spiramycin across the placental barrier is considered inefficient101, spiramycin is typically withdrawn once foetal transmission is confirmed and replaced with the conventional pyrimethamine and sulfadiazine regimen102. Furthermore, the drug is not suitable for treating toxoplasma encephalitis, as it cannot cross the blood-brain barrier103,104.
Polyether ionophores
Polyether ionophores such as monensin, narasin, salinomycin and lasalocid are secondary metabolites recovered from the fermentation of several Streptomyces species105,106, and are the predominant anti-coccidials used by the broiler industry since the 1970s to control and reduce the prevalence of coccidiosis in poultry107 and other livestock species. Studies suggest that these drugs inhibit host cell invasion and intracellular parasite development108,109, potentially by disrupting cation homeostasis110,111. The use of these natural products is now controlled by many poultry producers in the United States and subject to greater regulation in the European Union, partly due to the anti-bacterial activity of the ionophores and concerns about the potential spread of antimicrobial resistance co-selected to antibiotics of public health importance in human food products112,113. Public health risks associated with the use of the ionophores have been described as low114,115 but data is incomplete and ongoing surveillance of antimicrobial resistance and emergence of new risks is advocated116,117.
Paromomycin
Paromomycin is an aminoglycoside antibiotic isolated from Streptomyces rimosus forma paromomycinus118, and other species, with broad-spectrum activity against a number of bacteria and intestinal parasites69. In bacteria, the drug binds to ribosomal RNA and inhibits translocation during protein synthesis119, whereas in the kinetoplast Leishmania, it has been suggested to interfere with parasite mitochondrial activity120. Paromomycin first demonstrated potential against Cryptosporidium parvum in the early 1990s, however, its poor bioavailability when taken orally has limited its application for human use121,122,123. The drug was later evaluated in 1993 for efficacy in dairy calves, which showed that as a prophylactic, it was capable of reducing oocyst shedding and the severity of diarrhoea69. While studies have suggested that paromomycin inhibits the intracellular growth of C. parvum, the mechanism by which this occurs remains unclear121,122,123.
Oxytetracycline
Oxytetracycline (OTC), produced by Streptomyces rimosus, is a broad-spectrum antibiotic used widely in veterinary medicine since the early 1950s to treat bacterial and protozoal infections70,124,125. For Theileria infections in cattle, OTC has been used in conjunction with immunisation of a low infective dose of live parasites to reduce disease severity without inhibiting the development of natural immunity126. OTC was later shown to be effective against infection with Babesia in cattle, with high doses capable of completely inhibiting parasite replication and lower doses controlling parasitaemia while maintaining antibody responses127,128. The mechanism of action of OTC in these parasites has not been described, though it is likely similar to related tetracyclines like doxycycline, a suppressive anti-malarial prophylactic, which works against Plasmodium species by inhibiting protein synthesis in the apicoplast, leading to a subsequent loss of apicoplast function and a delayed, but potent, anti-malarial effect129.
Semi-synthetic antibiotics
Several antibiotics repurposed for use against apicomplexan parasites are synthetically modified analogues of natural products that target the translation of apicoplast proteins129,130,131. Doxycycline, for example, was chemically modified from OTC, and is now recommended for malaria prophylaxis by travellers entering malaria-endemic areas or occasionally as an alternative partner drug in ACTs where traditional combinations fail61. Clindamycin, derived from the microbial metabolite, lincomycin, is primarily administered as a safe and effective anti-malarial in the first trimester of pregnancy, or where traditional ACTs are unavailable61,132. The drug also acts as an alternative partner drug in combination therapies for toxoplasmosis patients who are intolerant to sulfonamides and pyrimethamine133,134, however, its efficacy against T. gondii is still controversial135.
Additionally, azithromycin, synthetically modified from the macrolide erythromycin, has been trialled as a treatment for cerebral toxoplasmosis in immunocompromised patients136, and as both a prophylactic and partner drug in malaria combination therapies137,138,139,140. However, there has been limited progress into clinical implementation as azithromycin’s efficacy in its current form is suboptimal compared with other clinically useful drugs140,141,142. Several studies have shown that further modification of azithromycin is capable of significantly improving the drug’s activity, making it of similar potency to fast-acting anti-malarials like chloroquine and artemisinin in vitro143,144,145,146.
Synthetic compounds with naturally occurring pharmacophores
Several natural products with demonstrated activity against apicomplexan parasites have not been pursued clinically for the treatment of human and animal diseases due to drug toxicity, or the emergence of new and more effective synthetic derivatives. For instance, many widely used drugs in human and veterinary medicine, such as chloroquine, atovaquone, buparvaquone and halofuginone, are synthetically made compounds that mimic key components of their natural counterparts.
Lapachol, first extracted from the bark of Tabebuia avellanedae trees in 1882, was one such natural product147. Like many other naphthoquinones, lapachol acts as an inhibitor of the mitochondrial electron transport chain and has shown efficacy in suppressing malaria in animals148,149. The identification of naphthoquinones as potential anti-malarial agents led to the discovery of more potent analogues like atovaquone150,151,152. Atovaquone was initially approved by the United States Food and Drug Administration (FDA) in 1995 as a monotherapy for malaria, but due to high rates of treatment failure driven by drug resistance, it was later combined with proguanil for malaria prophylaxis to reduce future resistance selection153,154. In addition to its anti-malarial activity, atovaquone has shown efficacy against other apicomplexan parasites, such as T. gondii155 and the zoonotic Babesia microti156. Parvaquone and buparvaquone also emerged as effective synthetic derivatives of lapachol and have been used to treat Theileria infections in cattle70. Buparvaquone has previously been shown to be more than 20-fold more active than parvaquone against T. parva and T. annulata, making it the preferred drug for treatment of African East Coast fever and tropical theileriosis in around 20 countries157.
Febrifugine, first isolated from the Chinese herbal plant, Dichroa febrifuga, is another natural product that demonstrated potent activity against Plasmodium spp. but was unable to be further developed for human use due to its low margin of safety and presence of unacceptable adverse effects158,159,160. Synthetic derivatives of febrifugine later yielded analogues like halofuginone, which was comparatively less toxic and developed commercially for veterinary use as a therapeutic and preventative agent for cryptosporidiosis in calves and coccidiosis in poultry160. Several studies reported that halofuginone reduces oocyst shedding of Cryptosporidium and Eimeria in cattle and chickens, significantly enhancing body weight gains when compared with untreated infected animals67,161,162. In Plasmodium spp., halofuginone is known to inhibit prolyl-tRNA synthetase163, and it is expected to have a similar effect in other apicomplexans164.
Current progress and challenges in drug discovery and development for apicomplexan parasites
While significant progress has been made to address the global health and economic burden of diseases caused by apicomplexans through both synthetic and natural therapeutic agents, these parasites continue to have a severe impact on human and animal health worldwide. The majority of the drugs currently used for treating these diseases are decades old, with drug resistance emerging as a major cause of treatment failure (Fig. 2). Resistance has now developed to all major classes of anti-malarials, including the current frontline ACTs16,17,18,19. The widespread reliance on anti-coccidials for prophylaxis and treatment in poultry farming has contributed to the selection of Eimeria strains resistant to all synthetic and natural anti-coccidials20,21,22. Although less prevalent, treatment failures have now been reported to buparvaquone in animals infected with T. annulata165 and mutations associated with sulfonamide resistance have been identified in clinical isolates of T. gondii166. Few alternatives with strong therapeutic potential are available. Currently, many of the natural products with activity against apicomplexan parasites target anti-microbial protein synthesis, and are typically used as suppressive preventative treatments rather than curative treatments due to their slow-acting mechanism of killing131. Therefore, there is an urgent need for next-generation drugs that are not only highly effective, preferably against multiple stages of the parasite’s lifecycle, but also selective with low likelihood of resistance selection.
Despite the ongoing global impact of apicomplexan parasites, only 11 new anti-parasitic drugs with apicomplexan activity have been approved for human use since 1981, and all are principally active against malaria23. In terms of anti-parasitic drugs for veterinary use, even fewer have become available due to cost-effectiveness being the over-riding consideration for development and use. Livestock diseases typically attract more attention for drug development when they pose a significant threat to profitable production and offer clear economic benefits following treatment167. For example, Eimeria, a major threat to intensive poultry production worldwide, has prompted the development of several anti-coccidial drugs, both natural and synthetic, to meet the growing demands in the poultry industry168, though only one new class (triazines) has been introduced in almost 40 years169. In contrast, diseases like babesiosis and theileriosis primarily affect livestock in tropical and subtropical regions, including parts of Africa and Asia where small-scale farming systems lack the financial resources to afford expensive treatments, regardless of their efficacy51. Therefore, treatment options for babesiosis and theileriosis are fewer and the incentive for dedicated drug development programs is less favourable. Other diseases like toxoplasmosis have often been overlooked as their economic impact is harder to quantify167,170, and infection in livestock is typically not detected until after abortions have occurred, by which point treatment offers little to no economic or animal health benefit76.
In recent years, partnerships with not-for-profit organisations (e.g. the Medicines for Malaria Venture, Drugs for Neglected Diseases), funding agencies, (e.g. Wellcome Trust, Bill and Melinda Gates Foundation), industries, and certain pharmaceutical companies, have made considerable contributions to the discovery of new drug candidates171. Several of these new drugs have reached late-stage clinical trials, including EDI048 for cryptosporidiosis172, and cipargamin, SJ733 and DSM265 for malaria173. Of note, cipargamin, is a synthetic compound featuring an indole group common to many natural products174, originally identified as NITD609 from a large library of pure natural products and synthetic compounds with natural product-derived structural features175. These spiroindolones now represent a new class of anti-malarials that inhibit the P. falciparum ATP4ase175,176. While most of these drugs are primarily intended for human use, some may have potential to be repurposed for the treatment of other apicomplexan infections in livestock due to common drug targets. Especially for neglected livestock diseases, drug repurposing may be an attractive and economical option, however, this could contribute to the selection and spread of drug resistance, which is of greatest public health importance with zoonotic apicomplexans.
Potential for development of natural products as next-generation drugs against apicomplexans
Given the historical importance of natural products for treating apicomplexan parasites, harnessing these compounds as an avenue for future drug development may provide a promising opportunity to discover novel chemical entities with therapeutic potential. Compared to conventional synthetic molecules, natural products are known to offer a broader range of chemical diversity and structural complexity177,178, typically featuring molecular scaffolds that have evolved to interact with proteins, enzymes and other biological molecules177,178. Many natural products and their semi-synthetic derivatives currently used to treat apicomplexan infections target protein synthesis in the parasite’s apicoplast and have been repurposed from their original use as anti-microbials. However, this approach carries the risk of contributing to resistance in other organisms and the environment, making it a less sustainable strategy for disease control. Therefore, screening for and identifying natural products with apicomplexan-specific mechanisms of action would offer a more promising alternative.
Several promising screens have been conducted with large compound and extract libraries sourced from plants, fungi, bacteria, and marine organisms against Plasmodium27,30,175,179,180, Cryptosporidium28,181,182, Toxoplasma183,184,185,186, Eimeria187,188,189,190, and Babesia191,192,193 (Table 4). These studies have led to the identification of a number of bioactive compounds with low cytotoxicity, some of which have known activity in other systems, whereas others are entirely novel. With over 400,000 unique natural compounds already curated to date26, there remains significant scope to build upon existing screens against apicomplexans and repurpose promising natural products. Most notably, these studies highlight the incredible diversity and untapped potential of bioactive compounds from a wide array of natural sources yet to be discovered. This offers an exciting pathway forward for drug discovery and development, not only against the six genera covered in detail in this review, but also against other apicomplexans like Neospora76, Sarcocystis194, and Besnoitia195, which lack effective treatment options and pose significant health and economic challenges in livestock.
Despite the successful examples of natural products for treating apicomplexan parasites, several intrinsic challenges may have contributed to a decline in their consideration as therapeutic agents. Critically important to drug development efforts is the issue of large-scale drug supply. While in vitro efficacy testing can be achieved with milligram quantities of a compound, larger amounts, in the order of grams, are typically needed for downstream studies to comprehensively evaluate compound potential as a viable drug candidate196. This becomes a major challenge when the natural products of interest are derived from microbes that cannot be cultured under standard laboratory conditions197. Given that over 99% of bacteria from environmental samples are unculturable, discovering and developing entirely new scaffolds with novel mechanisms of action becomes an even greater obstacle198. Furthermore, many promising natural products require chemical optimisation to reduce cytotoxicity and improve pharmacokinetic and pharmacodynamic properties, as was the case with quinine, artemisinin, lapachol and febrifugine, among others. While lapachol and febrifugine are relatively small and non-complex, generating structurally diverse analogues of larger and more complex natural products through synthetic chemistry can be a challenging and resource-intensive process that may not be economically realistic, especially for apicomplexan diseases in livestock199. Encouragingly, following the example of the synthetic optimisation of erythromycin to azithromycin200,201, whose importance is demonstrated by being on the WHO list of essential medicines78, successful synthetic optimisation of complex natural products is possible and can enhance their pharmacology, efficacy, safety and cost of production.
Recent advances in synthetic biology may offer new pathways to enhance the feasibility and scalability of natural product drug development. These methods involve introducing and expressing biosynthetic genes from native producers in host organisms that are easier to culture and genetically manipulate, allowing increased yields of valuable and difficult-to-obtain compounds202,203. Additionally, attempts to engineer certain enzymes by synthetic biology have demonstrated the potential to generate new natural product derivatives203,204, which may be useful in cases where promising natural scaffolds are not feasibly modifiable by synthetic chemistry. However, these methods are still in their early stages and require wider testing to establish utility in the field of natural product drug discovery and development.
Conclusions
Apicomplexan parasites continue to impose a significant global health and economic burden through widespread diseases affecting both human health and livestock welfare and productivity. Moreover, the emergence of drug resistance to existing treatments poses an additional challenge in managing these infections. Given the historical success of natural products and the abundance of naturally occurring sources still yet to be explored, there remains considerable potential to identify new drug candidates against apicomplexans, both from currently available compound libraries and from novel natural products discovered through innovative identification programs covering a diverse range of plants, fungi, bacteria, and marine organisms205,206,207. However, despite the substantial disease burden of these parasites, the financial incentives for drug development may be limited for many apicomplexan diseases unless the drug has a low cost of production and offers excellent efficacy and safety with a practical dosage regimen to ensure treatment adherence, especially for those that primarily affect low- and middle- income countries. Recent technological advancements in areas like synthetic biology may offer an opportunity to make natural product drug development and production more affordable and feasible for diseases with low research investment. To fully optimise the potential of natural products, discovery and screening efforts should be combined with modern medicinal chemistry to help optimise the efficacy, scalability and development of new drugs, ultimately improving the likelihood of successful market translation. Therefore, revisiting natural products as a source of next-generation drugs remains a valuable pathway forward to address the growing global health and economic burden caused by apicomplexan parasites in humans and livestock.
Data availability
No datasets were generated or analysed during the current study.
References
Rojas-Pirela, M. et al. Congenital Transmission of Apicomplexan Parasites: A Review. Front. Microbiol. 12, 751648 (2021).
Katris, N. J. et al. The Apical Complex Provides a Regulated Gateway for Secretion of Invasion Factors in Toxoplasma. PLOS Pathog 10, e1004074 (2014).
Verhoef, J. M. J., Meissner, M. & Kooij, T. W. A. Organelle Dynamics in Apicomplexan Parasites. mBio 12, e01409–e01421 (2021).
Gubbels, M. J. & Duraisingh, M. T. Evolution of apicomplexan secretory organelles. Int J. Parasitol. 42, 1071–1081 (2012).
Ibrahim, H. M. & Sander, V. A. Editorial: Apicomplexa Epidemiology, Control, Vaccines and Their Role in Host-Pathogen Interaction. Front Vet. Sci. 9, 885181 (2022).
World Health Organization. WHO guidelines for malaria. (Geneva, 2022).
Munhenga, G., Masendu, H. T., Brooke, B. D., Hunt, R. H. & Koekemoer, L. K. Pyrethroid resistance in the major malaria vector Anopheles arabiensis from Gwave, a malaria-endemic area in Zimbabwe. Malar. J. 7, 247 (2008).
Toé, K. H. et al. Increased pyrethroid resistance in malaria vectors and decreased bed net effectiveness, Burkina Faso. Emerg. Infect. Dis. 20, 1691–1696 (2014).
Smith, L. B., Kasai, S. & Scott, J. G. Pyrethroid resistance in Aedes aegypti and Aedes albopictus: Important mosquito vectors of human diseases. Pestic. Biochem. Physiol. 133, 1–12 (2016).
Amadi, B. et al. High dose prolonged treatment with nitazoxanide is not effective for cryptosporidiosis in HIV positive Zambian children: a randomised controlled trial. BMC Infect. Dis. 9, 195 (2009).
Abubakar, I., Aliyu, S. H., Arumugam, C., Hunter, P. R. & Usman, N. K. Prevention and treatment of cryptosporidiosis in immunocompromised patients. Cochrane Database Syst Rev, Cd004932 (2007).
Araujo, F. G., Shepard, R. M. & Remington, J. S. In vivo activity of the macrolide antibiotics azithromycin, roxithromycin and spiramycin against Toxoplasma gondii. Eur. J. Clin. Microbiol. Infect. Dis 10, 519–524 (1991).
Chamberland, S., Kirst, H. A. & Current, W. L. Comparative activity of macrolides against Toxoplasma gondii demonstrating utility of an in vitro microassay. Antimicrob. Agents Chemother. 35, 903–909 (1991).
Nguyen, B. T. & Stadtsbaeder, S. Comparative effects of cotrimoxazole (trimethoprim-sulphamethoxazole), pyrimethamine-sulphadiazine and spiramycin during avirulent infection with Toxoplasma gondii (Beverley strain) in mice. Br. J. Pharm. 79, 923–928 (1983).
Haverkos, H. W. Assessment of therapy for toxoplasma encephalitis: The TE study group. Am. J. Med. 82, 907–914 (1987).
Pulcini, S. et al. Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, enlarge the parasite’s food vacuole and alter drug sensitivities. Sci. Rep. 5, 14552 (2015).
Petersen, I., Eastman, R. & Lanzer, M. Drug-resistant malaria: Molecular mechanisms and implications for public health. FEBS Lett. 585, 1551–1562 (2011).
Imwong, M. et al. The spread of artemisinin-resistant Plasmodium falciparum in the Greater Mekong subregion: a molecular epidemiology observational study. Lancet Infect. Dis. 17, 491–497 (2017).
World Health Organization. World malaria report 2022. (Geneva, 2022).
Jeffers, T. K. Eimeria tenella: Incidence, Distribution, and Anticoccidial Drug Resistance of Isolants in Major Broiler-Producing Areas. Avian Dis 18, 74–84 (1974).
Jeffers, T. K. Eimeria acervulina and E. maxima: incidence and anticoccidial drug resistance of isolants in major broiler-producing areas. Avian Dis 18, 331–342 (1974).
Jeffers, T. K. Anticoccidial Drug Resistance: Differences Between Eimeria acervulina and E. tenella Strains Within Broiler Houses. Poult. Sci. 53, 1009–1013 (1974).
Newman, D. J. & Cragg, G. M. Natural Products as Sources of New Drugs over the Nearly Four Decades from 01/1981 to 09/2019. J. Nat. Products 83, 770–803 (2020).
Liao, F. Discovery of Artemisinin (Qinghaosu). Molecules 14, 5362–5366 (2009).
NobelPrize.org. The Nobel Prize in Physiology or Medicine 2015, https://www.nobelprize.org/prizes/medicine/2015/tu/facts/ (2024).
Gallo, K. et al. SuperNatural 3.0—a database of natural products and natural product-based derivatives. Nucleic Acids Res. 51, D654–D659 (2022).
Wright, A. E. et al. Antiplasmodial Compounds from Deep-Water Marine Invertebrates. Mar Drugs, 19, https://doi.org/10.3390/md19040179 (2021).
Bone Relat, R. M. et al. High-Throughput Screening of a Marine Compound Library Identifies Anti-Cryptosporidium Activity of Leiodolide A. Mar Drugs, 20, https://doi.org/10.3390/md20040240 (2022).
Hoepfner, D. et al. Selective and Specific Inhibition of the Plasmodium falciparum Lysyl-tRNA Synthetase by the Fungal Secondary Metabolite Cladosporin. Cell Host Microbe 11, 654–663 (2012).
Fernandez, L. S., Jobling, M. F., Andrews, K. T. & Avery, V. M. Antimalarial activity of natural product extracts from Papua New Guinean and Australian plants against Plasmodium falciparum. Phytother. Res. 22, 1409–1412 (2008).
World Health Organization. World malaria report 2024. (Geneva, 2024).
Feher, M. & Schmidt, J. M. Property Distributions: Differences between Drugs, Natural Products, and Molecules from Combinatorial Chemistry. J. Chem. Inf. Comput. Sci. 43, 218–227 (2003).
Jumani, R. S. et al. Opportunities and Challenges in Developing a Cryptosporidium Controlled Human Infection Model for Testing Antiparasitic Agents. ACS Infect. Dis. 7, 959–968 (2021).
Tenter, A. M., Heckeroth, A. R. & Weiss, L. M. Toxoplasma gondii: from animals to humans. Int. J. Parasitol 30, 1217–1258 (2000).
Luft, B. J. et al. Toxoplasmic Encephalitis in Patients with the Acquired Immunodeficiency Syndrome. N. Engl. J. Med. 329, 995–1000 (1993).
Arruda, S. et al. Clinical manifestations and visual outcomes associated with ocular toxoplasmosis in a Brazilian population. Sci. Rep. 11, 3137 (2021).
Sanchez, S. G. & Besteiro, S. The pathogenicity and virulence of Toxoplasma gondii. Virulence 12, 3095–3114 (2021).
Flegr, J. & Horáček, J. Negative Effects of Latent Toxoplasmosis on Mental Health. Front Psychiatry 10, 1012 (2019).
Alvarado-Esquivel, C. et al. Association Between Toxoplasma gondii Exposure and Heart Disease: A Case-Control Study. J. Clin. Med. Res 8, 402–409 (2016).
Contopoulos-Ioannidis, D. G., Gianniki, M., Truong, A. A. N. & Montoya, J. G. Toxoplasmosis and Schizophrenia: A Systematic Review and Meta-Analysis of Prevalence and Associations and Future Directions. Psychiatr. Res. Clin. Pract. 4, 48–60 (2022).
Khademvatan, S. et al. Association of Toxoplasma gondii infection with cardiovascular diseases: a cross-sectional study among patients with heart failure diseases in Urmia, North-West of Iran. Ann. Parasitol 66, 193–199 (2020).
Henker, L. C. et al. Abortion outbreak in a sheep flock caused by Toxoplasma gondii clonal type III. Parasitol. Res. 121, 2633–2639 (2022).
Dennis, S. M. Perinatal lamb mortality in Western Australia 3. Congenital Infections. Aust. Vet. J. 50, 507–510 (1974).
Osborne, H. G. Abortion in sheep associated with Toxoplasma. Aust. Vet. J 35, 424–425 (1959).
Schröder, J. In Apicomplexa in Livestock (ed A. Lainsbury, McCann, E.) 36–78 (CABI, 2023).
Bowman, D. D. In Georgis’ Parasitology for Veterinarians (Eleventh Edition) (ed Dwight. D. Bowman) 90-134 (W.B. Saunders, 2021).
Blake, D. P. et al. Re-calculating the cost of coccidiosis in chickens. Vet. Res. 51, 115 (2020).
Roblin, M. et al. Study of the economic impact of cryptosporidiosis in calves after implementing good practices to manage the disease on dairy farms in Belgium, France, and the Netherlands. Curr. Res. Parasitol. Vector-Borne Dis. 4, 100149 (2023).
McLeod, R. & Kristjanson, P. Economic Impact of Ticks and Tick-Borne Diseases to Livestock in Africa, Asia and Australia. (Australian Centre for International Agricultural Research, 1999).
Joel G. Breman, A. E., and Gerald T. Keusch. In American Journal of Tropical Medicine and Hygiene. Vol. 64 (ed Andréa Egan Joel G. Breman, and Gerald T. Keusch.) (Northbrook, 2001).
Ghafar, A. et al. In Advances in Parasitology Vol. 114 (eds David Rollinson & Russell Stothard) 167-244 (Academic Press, 2021).
RTS, S Clinical Trials Partnership Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. Lancet 386, 31–45 (2015).
Datoo, M. S. et al. Efficacy and immunogenicity of R21/Matrix-M vaccine against clinical malaria after 2 years’ follow-up in children in Burkina Faso: a phase 1/2b randomised controlled trial. Lancet Infect. Dis. 22, 1728–1736 (2022).
Buxton, D. & Innes, E. A. A commercial vaccine for ovine toxoplasmosis. Parasitology 110, S11–S16 (1995).
Meat & Livestock Australia Limited. Development of an improved frozen substitute for chilled tick fever vaccine for cattle. (Sydney, NSW, Australia, 2010).
Zaheer, T. et al. Vaccines against chicken coccidiosis with particular reference to previous decade: progress, challenges, and opportunities. Parasitol. Res 121, 2749–2763 (2022).
Timmermans, M. et al. The first commercially approved efficacious Cryptosporidium vaccine protecting New-Born calves from severe diarrhea. Vet. Vaccin. 3, 100054 (2024).
Furtado, J. M., Smith, J. R., Belfort, R. Jr., Gattey, D. & Winthrop, K. L. Toxoplasmosis: a global threat. J. Glob. Infect. Dis. 3, 281–284 (2011).
Tenter, A. M. Toxoplasma gondii in animals used for human consumption. Memórias do Instituto Oswaldo Cruz 104 (2009).
Schröder, J. In Apicomplexa in Livestock (ed A. Lainsbury, McCann, E.) 257-289 (CABI, 2023).
World Health Organization. Guidelines for the treatment of malaria. (Geneva, 2015).
Achan, J. et al. Quinine, an old anti-malarial drug in a modern world: role in the treatment of malaria. Malar. J. 10, 144 (2011).
Payne, D. Spread of chloroquine resistance in Plasmodium falciparum. Parasitol. Today 3, 241–246 (1987).
Lin, J. T., Juliano, J. J. & Wongsrichanalai, C. Drug-Resistant Malaria: The Era of ACT. Curr. Infect. Dis. Rep. 12, 165–173 (2010).
Yapar, N., Erdenizmenli, M., Oğuz, V. A., Çakır, N. & Yüce, A. Cerebral toxoplasmosis treated with clindamycin alone in an HIV-positive patient allergic to sulfonamides. Int. J. Infect. Dis. 9, 64–66 (2005).
Trotz-Williams, L. A., Jarvie, B. D., Peregrine, A. S., Duffield, T. F. & Leslie, K. E. Efficacy of halofuginone lactate in the prevention of cryptosporidiosis in dairy calves. Vet. Rec. 168, 509–509 (2011).
Lefay, D., Naciri, M., Poirier, P. & Chermette, R. Efficacy of halofuginone lactate in the prevention of cryptosporidiosis in suckling calves. Vet. Rec. 148, 108–112 (2001).
Naciri, M., Mancassola, R., Yvoré, P. & Peeters, J. E. The effect of halofuginone lactate on experimental Cryptosporidium parvum infections in calves. Vet. Parasitol. 45, 199–207 (1993).
Fayer, R. & Ellis, W. Paromomycin is effective as prophylaxis for cryptosporidiosis in dairy calves. J. Parasitol. 79, 771–774 (1993).
Davis, J. L. & Gookin, J. L. In Veterinary Pharmacology and Therapeutics (Tenth Edition) (eds J. Edmond Riviere & Mark G. Papich) 1128-1165 (John Wiley & Sons, 2018).
Mosqueda, J., Olvera-Ramirez, A., Aguilar-Tipacamu, G. & Canto, G. J. Current advances in detection and treatment of babesiosis. Curr. Med Chem. 19, 1504–1518 (2012).
Nagar, J., Gurjar, T. & Mali, M. Therapeutic management of theileriosis in bovines. J. Entomol. Zool. Stud. 7, 495–497 (2018).
Andrews, A. Coccidiosis of Pigs, https://www.msdvetmanual.com/digestive-system/coccidiosis/coccidiosis-of-pigs (2022).
Mundt, H. C., Daugschies, A., Wüstenberg, S. & Zimmermann, M. Studies on the efficacy of toltrazuril, diclazuril and sulphadimidine against artificial infections with Isospora suis in piglets. Parasitol. Res. 90, S160–S162 (2003).
Batey, R., Nilon, P., Page, S., Browning, G. & Norris, J. Antimicrobial prescribing guidelines for sheep. Aust. Vet. J. 102, 103–142 (2024).
Sánchez-Sánchez, R., Vázquez, P., Ferre, I. & Ortega-Mora, L. M. Treatment of Toxoplasmosis and Neosporosis in Farm Ruminants: State of Knowledge and Future Trends. Curr. Top. Med Chem. 18, 1304–1323 (2018).
Newman, D. J. & Cragg, G. M. Natural Products as Sources of New Drugs from 1981 to 2014. J. Nat. Products 79, 629–661 (2016).
World Health Organization. World Health Organization Model List of Essential Medicines - 23rd List. (Geneva, 2023).
Andersag, H., Breitner, S., Jung, H. & Farbenind, I. G. Process for the preparation of a quinoline compound containing a basic substituted amino group in the 4-position. German Patent. patent (1937).
Andersag, H., Breitner, S. & Jung, H. Quinoline compound and process of making the same. German Patent. patent (1941).
Coatney, G. R. Pitfalls in a Discovery: The Chronicle of Chloroquine. Am. J. Tropical Med. Hyg. 12, 121–128 (1963).
Trenholme, G. M. et al. Mefloquine (WR 142,490) in the Treatment of Human Malaria. Science 190, 792–794 (1975).
Elderfield, R. C., Mertel, H. E., Mitch, R. T., Wempen, I. M. & Werble, E. Synthesis of Primaquine and Certain of its Analogs1. J. Am. Chem. Soc. 77, 4816–4819 (1955).
Nyunt, M. & Plowe, C. V. In Pharmacology and Therapeutics (eds Scott A. Waldman et al.) 1141-1170 (W.B. Saunders, 2009).
Fitch, C. D. Involvement of heme in the antimalarial action of chloroquine. Trans. Am. Clin. Climatol. Assoc. 109, 97–105 (1998). discussion 105-106.
Fong, K. Y. & Wright, D. W. Hemozoin and antimalarial drug discovery. Future Med Chem. 5, 1437–1450 (2013).
Sullivan, D. J. Jr., Matile, H., Ridley, R. G. & Goldberg, D. E. A Common Mechanism for Blockade of Heme Polymerization by Antimalarial Quinolines. J. Biol. Chem. 273, 31103–31107 (1998).
Qinghaosu, A. C. R. G. Antimalaria Studies On Qinghaosu. Chin. Med. J. 92, 811–816 (1979).
Jiang, J.-B., Guo, X.-B., Li, G.-Q., Cheung Kong, Y. & Arnold, K. Antimalarial activity of mefloquine and Qinghaosu. Lancet 320, 285–288 (1982).
Li, G., Guo, X., Arnold, K., Jian, H. & Fu, L. Randomised comparative study of mefloquine, Qinghaosu, and pyrimethamine-sulfadoxine in patients with falciparum malaria. Lancet 324, 1360–1361 (1984).
Tu, Y. The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine. Nat. Med. 17, 1217–1220 (2011).
Adebayo, J. O. et al. Enhancing the antimalarial activity of artesunate. Parasitol. Res. 119, 2749–2764 (2020).
Tilley, L., Straimer, J., Gnädig, N. F., Ralph, S. A. & Fidock, D. A. Artemisinin Action and Resistance in Plasmodium falciparum. Trends Parasitol 32, 682–696 (2016).
Pinnert-Sindico, S. A new species of Streptomyces producing antibiotics Streptomyces ambofaciens n. sp., cultural characteristics. Ann. Inst. Pasteur ((Paris)) 87, 702–707 (1954).
Pfefferkorn, E. R. & Borotz, S. E. Comparison of mutants of Toxoplasma gondii selected for resistance to azithromycin, spiramycin, or clindamycin. Antimicrob. Agents Chemother. 38, 31–37 (1994).
Chodos, J. B. & Habegger-Chodos, H. E. The Treatment of Ocular Toxoplasmosis with Spiramycin. Arch. Ophthalmol. 65, 401–409 (1961).
Peters, P. J., Thigpen, M. C., Parise, M. E. & Newman, R. D. Safety and Toxicity of Sulfadoxine/Pyrimethamine. Drug Saf. 30, 481–501 (2007).
Hotop, A., Hlobil, H. & Groß, U. Efficacy of Rapid Treatment Initiation Following Primary Toxoplasma gondii Infection During Pregnancy. Clin. Infect. Dis. 54, 1545–1552 (2012).
Desmonts, G. & Couvreur, J. Toxoplasmosis in pregnancy and its transmission to the fetus. Bull. N. Y Acad. Med 50, 146–159 (1974).
Weiss, L. M. & Dubey, J. P. Toxoplasmosis: A history of clinical observations. Int J. Parasitol. 39, 895–901 (2009).
Forestier, F., Daffos, F., Rainaut, M., Desnottes, J. F. & Gaschard, J. C. Fetomaternal therapeutic follow-up of spiramycin during pregnancy]. Arch. Fr. Pediatr. 44, 539–544 (1987).
Goldstein, E. J. C., Montoya, J. G. & Remington, J. S. Management of Toxoplasma gondii Infection during Pregnancy. Clin. Infect. Dis. 47, 554–566 (2008).
McCarthy, J. S., Wortmann, G. W. & Kirchhoff, L. V. In Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases (Eighth Edition) (eds John E. Bennett, Raphael Dolin, & Martin J. Blaser) 510-518.e513 (W.B. Saunders, 2015).
Schoondermark-Van de Ven, E. et al. Effectiveness of spiramycin for treatment of congenital Toxoplasma gondii infection in rhesus monkeys. Antimicrobial Agents Chemother 38, 1930–1936 (1994).
Agtarap, A., Chamberlin, J. W., Pinkerton, M. & Steinrauf, L. K. Structure of monensic acid, a new biologically active compound. J. Am. Chem. Soc. 89, 5737–5739 (1967).
Berg, D. H. & Hamill, R. L. The isolation and characterization of narasin, a new polyether antibiotic. J. Antibiot. ((Tokyo)) 31, 1–6 (1978).
Biely, J. Monensin in Broiler Rations. Avian Dis. 17, 362–368 (1973).
Augustine, P. C., Smith, C. K., Danforth, H. D. & Ruff, M. D. Effect of Ionophorous Anticoccidials on Invasion and Development of Eimeria: Comparison of Sensitive and Resistant Isolates and Correlation with Drug Uptake. Poult. Sci. 66, 960–965 (1987).
Smith, C. K. & Strout, R. G. Eimeria tenella: accumulation and retention of anticoccidial ionophores by extracellular sporozoites. Exp. Parasitol. 48, 325–330 (1979).
Smith, C. K., Galloway, R. B. & White, S. L. Effect of ionophores on survival, penetration, and development of Eimeria tenella sporozoites in vitro. J. Parasitol. 67, 511–516 (1981).
Smith, C. K. & Galloway, R. B. Influence of monensin on cation influx and glycolysis of Eimeria tenella sporozoites in vitro. J. Parasitol. 69, 666–670 (1983).
Cervantes, H. M. & McDougald, L. R. Raising broiler chickens without ionophore anticoccidials. J. Appl. Poult. Res. 32, 100347 (2023).
World Health Organization. Antimicrobial Resistance Global Report On Surveillance. (Geneva, 2014).
Callaway, T. R. et al. Ionophores: their use as ruminant growth promotants and impact on food safety. Curr. Issues Intest Microbiol. 4, 43–51 (2003).
Dorne, J. L. C. M. et al. Risk assessment of coccidostatics during feed cross-contamination: Animal and human health aspects. Toxicol. Appl. Pharmacol. 270, 196–208 (2013).
Carresi, C., Marabelli, R., Roncada, P. & Britti, D. Is the Use of Monensin Another Trojan Horse for the Spread of Antimicrobial Resistance?. Antibiotics 13, 129 (2024).
Frederiksen, R. F. et al. Polyether ionophore resistance in a one health perspective. Frontiers in Microbiology 15, https://doi.org/10.3389/fmicb.2024.1347490 (2024).
Roger. P. Frohardt, T. H. H., Ehrlich. John, Knudsen. Mildred. Penner. Antibiotic and methods for obtaining same. U.S. Patent. patent (1959).
Fourmy, D., Yoshizawa, S. & Puglisi, J. D. Paromomycin binding induces a local conformational change in the A-site of 16 s rRNA11Edited by I. Tinoco. J. Mol. Biol. 277, 333–345 (1998).
Maarouf, M., de Kouchkovsky, Y., Brown, S., Petit, P. X. & Robert-Gero, M. In vivo interference of paromomycin with mitochondrial activity of Leishmania. Exp. Cell Res 232, 339–348 (1997).
Marshall, R. J. & Flanigan, T. P. Paromomycin Inhibits Cryptosporidium Infection of a Human Enterocyte Cell Line. J. Infect. Dis. 165, 772–774 (1992).
Armitage, K. et al. Treatment of cryptosporidiosis with paromomycin. A report of five cases. Arch. Intern Med 152, 2497–2499 (1992).
Griffiths, J. K., Balakrishnan, R., Widmer, G. & Tzipori, S. Paromomycin and geneticin inhibit intracellular Cryptosporidium parvum without trafficking through the host cell cytoplasm: implications for drug delivery. Infect. Immun. 66, 3874–3883 (1998).
Cross, T. Streptomyces Species producing Oxytetracycline. Nature 195, 832–833 (1962).
Scheidy, S. F. Recent advances in veterinary chemotherapy. Can. J. Comp. Med Vet. Sci. 15, 54–61 (1951).
Radley, D. E. in Advances in the Control of Theileriosis: Proceedings of an International Conference held at the International Laboratory for Research on Animal Diseases in Nairobi, 9–13th February, 1981 (eds A. D. Irvin, M. P. Cunningham, & A. S. Young) 227-237 (Springer Netherlands, 1981).
Taylor, S. M., Elliott, C. T. & Kenny, J. Inhibition of Babesia divergens in cattle by oxytetracycline. Vet. Rec. 118, 98–102 (1986).
Pipano, E., Markovics, A., Kriegel, Y., Frank, M. & Fish, L. Use of long-acting oxytetracycline in the immunisation of cattle against Babesia bovis and B. bigemina. Res Vet. Sci. 43, 64–66 (1987).
Dahl, E. L. et al. Tetracyclines specifically target the apicoplast of the malaria parasite Plasmodium falciparum. Antimicrob. Agents Chemother. 50, 3124–3131 (2006).
McFadden, G. I., Reith, M. E., Munholland, J. & Lang-Unnasch, N. Plastid in human parasites. Nature 381, 482–482 (1996).
Dahl, E. L. & Rosenthal, P. J. Multiple antibiotics exert delayed effects against the Plasmodium falciparum apicoplast. Antimicrob. Agents Chemother. 51, 3485–3490 (2007).
Obonyo, C. O., Juma, E. A., Were, V. O. & Ogutu, B. R. Efficacy of 3-day low dose quinine plus clindamycin versus artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in Kenyan children (CLINDAQUINE): an open-label randomized trial. Malar. J. 21, 30 (2022).
Dannemann, B. R., Israelski, D. M. & Remington, J. S. Treatment of Toxoplasmic Encephalitis With Intravenous Clindamycin. Arch. Intern. Med. 148, 2477–2482 (1988).
Madi, D., Achappa, B., Rao, S., Ramapuram, J. T. & Mahalingam, S. Successful treatment of cerebral toxoplasmosis with clindamycin: a case report. Oman Med. J 27, 411–412 (2012).
Rajapakse, S., Chrishan Shivanthan, M., Samaranayake, N., Rodrigo, C. & Deepika Fernando, S. Antibiotics for human toxoplasmosis: a systematic review of randomized trials. Pathog. Glob. Health 107, 162–169 (2013).
Pham, J. V. et al. A Review of the Microbial Production of Bioactive Natural Products and Biologics. Front. Microbiol.10, https://doi.org/10.3389/fmicb.2019.01404 (2019).
Noedl, H. et al. Azithromycin combination therapy with artesunate or quinine for the treatment of uncomplicated Plasmodium falciparum malaria in adults: a randomized, phase 2 clinical trial in Thailand. Clin. Infect. Dis. 43, 1264–1271 (2006).
Ohrt, C., Willingmyre, G. D., Lee, P., Knirsch, C. & Milhous, W. Assessment of azithromycin in combination with other antimalarial drugs against Plasmodium falciparum in vitro. Antimicrob. Agents Chemother. 46, 2518–2524 (2002).
Sykes, A. et al. Azithromycin plus artesunate versus artemether-lumefantrine for treatment of uncomplicated malaria in Tanzanian children: a randomized, controlled trial. Clin. Infect. Dis. 49, 1195–1201 (2009).
Taylor, W. R. et al. Malaria prophylaxis using azithromycin: a double-blind, placebo-controlled trial in Irian Jaya, Indonesia. Clin. Infect. Dis. 28, 74–81 (1999).
Andersen, S. L. et al. Successful double-blinded, randomized, placebo-controlled field trial of azithromycin and doxycycline as prophylaxis for malaria in western Kenya. Clin. Infect. Dis. 26, 146–150 (1998).
Krudsood, S. et al. A randomized clinical trial of combinations of artesunate and azithromycin for treatment of uncomplicated Plasmodium falciparum malaria in Thailand. Southeast Asian J. Trop. Med Public Health 31, 801–807 (2000).
Burns, A. L. et al. Retargeting azithromycin analogues to have dual-modality antimalarial activity. BMC Biol. 18, 133 (2020).
Wilson, D. W. et al. Macrolides rapidly inhibit red blood cell invasion by the human malaria parasite, Plasmodium falciparum. BMC Biol 13, 52 (2015).
Bukvić Krajačić, M. et al. Synthesis, structure-activity relationship, and antimalarial activity of ureas and thioureas of 15-membered azalides. J. Med Chem. 54, 3595–3605 (2011).
Peric, M. et al. A novel class of fast-acting antimalarial agents: Substituted 15-membered azalides. Br. J. Pharm. 178, 363–377 (2021).
Hussain, H., Krohn, K., Ahmad, V., Miana, G. & Green, I. Lapachol: An Overview. ARKIVOC: archive for organic chemistry, 145-171 (2007).
Ball, E. G., Anfinsen, C. B. & Cooper, O. The inhibitory action of naphthoquinones on respiratory processes. J. Biol. Chem. 168, 257–270 (1947).
Fieser, L. F. & Richardson, A. P. Naphthoquinone antimalarials; correlation of structure and activity against P. lophurae in ducks. J. Am. Chem. Soc. 70, 3156–3165 (1948).
Hudson, A. T. et al. 566C80: a potent broad spectrum anti-infective agent with activity against malaria and opportunistic infections in AIDS patients. Drugs Exp. Clin. Res 17, 427–435 (1991).
De Andrade-Neto, V. F. et al. Antimalarial activity of phenazines from lapachol, β-lapachone and its derivatives against Plasmodium falciparum in vitro and Plasmodium berghei in vivo. Bioorg. Med. Chem. Lett. 14, 1145–1149 (2004).
Moreira, D. R. M. et al. Evaluation of naphthoquinones identified the acetylated isolapachol as a potent and selective antiplasmodium agent. J. Enzym. Inhibition Med. Chem. 30, 615–621 (2015).
Vaidya, A. B. & Mather, M. W. Atovaquone resistance in malaria parasites. Drug Resistance Updates 3, 283–287 (2000).
Chiodini, P. L. et al. Evaluation of atovaquone in the treatment of patients with uncomplicated Plasmodium falciparum malaria. J. Antimicrobial Chemother 36, 1073–1078 (1995).
Kovacs, J. A. Efficacy of atovaquone in treatment of toxoplasmosis in patients with AIDS. NIAID-Clin. Cent. Intramural AIDS Program. Lancet 340, 637–638 (1992).
Hughes, W. T. & Oz, H. S. Successful prevention and treatment of babesiosis with atovaquone. J. Infect. Dis. 172, 1042–1046 (1995).
Carter, P. Assessment of the efficacy of Buparvaquone for the treatment of ‘benign’ bovine theileriosis. (Meat & Livestock Australia Limited, Sydney, 2011).
Jang, C. S., Fu, F. Y., Huang, K. C. & Wang, C. Y. Pharmacology of Ch’ang Shan (Dichroa febrifuga), a Chinese Antimalarial Herb. Nature 161, 400–401 (1948).
Koepfli, J. B., Mead, J. F. & Brockman, J. A. Jr. An alkaloid with high antimalarial activity from Dichroa febrifuga. J. Am. Chem. Soc. 69, 1837–1837 (1947).
Jiang, S. et al. Antimalarial Activities and Therapeutic Properties of Febrifugine Analogs. Antimicrobial Agents Chemother. 49, 1169–1176 (2005).
Jarvie, B. D. et al. Effect of halofuginone lactate on the occurrence of Cryptosporidium parvum and growth of neonatal dairy calves. J. Dairy Sci. 88, 1801–1806 (2005).
Zhang, D. F. et al. Anticoccidial effect of halofuginone hydrobromide against Eimeria tenella with associated histology. Parasitol. Res. 111, 695–701 (2012).
Tye, M. A. et al. Elucidating the path to Plasmodium prolyl-tRNA synthetase inhibitors that overcome halofuginone resistance. Nat. Commun. 13, 4976 (2022).
Jain, V. et al. Targeting Prolyl-tRNA Synthetase to Accelerate Drug Discovery against Malaria, Leishmaniasis, Toxoplasmosis, Cryptosporidiosis, and Coccidiosis. Structure 25, 1495–1505.e1496 (2017).
Mhadhbi, M. et al. In vivo evidence for the resistance of Theileria annulata to buparvaquone. Vet. Parasitol. 169, 241–247 (2010).
Aspinall, T. V., Joynson, D. H., Guy, E., Hyde, J. E. & Sims, P. F. The molecular basis of sulfonamide resistance in Toxoplasma gondii and implications for the clinical management of toxoplasmosis. J. Infect. Dis. 185, 1637–1643 (2002).
Schröder, J. In Apicomplexa in Livestock (ed A. Lainsbury, McCann, E.) 1–9 (CABI, 2023).
Alexandratos, N. & Bruinsma, J. (Agricultural & Applied Economics Association (AAEA), St. Paul, 2012).
McDougald, L. R. In Diseases of Poultry, Fourteenth Edition (ed David E. Swayne) Ch. 28, (John Wiley & Sons, Inc., 2020).
Ahmad, R. et al. Management and control of coccidiosis in poultry - A review. Anim. Biosci. 37, 1–15 (2024).
Rao, S. P. S., Manjunatha, U. H., Mikolajczak, S., Ashigbie, P. G. & Diagana, T. T. Drug discovery for parasitic diseases: powered by technology, enabled by pharmacology, informed by clinical science. Trends Parasitol. 39, 260–271 (2023).
Manjunatha, U. H. et al. Cryptosporidium PI(4)K inhibitor EDI048 is a gut-restricted parasiticidal agent to treat paediatric enteric cryptosporidiosis. Nat. Microbiol. 9, 2817–2835 (2024).
Siqueira-Neto, J. L. et al. Antimalarial drug discovery: progress and approaches. Nat. Rev. Drug Discov. 22, 807–826 (2023).
Umer, S. M., Solangi, M., Khan, K. M. & Saleem, R. S. Z. Indole-Containing Natural Products 2019-2022: Isolations, Reappraisals, Syntheses, and Biological Activities. Molecules 27, https://doi.org/10.3390/molecules27217586 (2022).
Rottmann, M. et al. Spiroindolones, a Potent Compound Class for the Treatment of Malaria. Science 329, 1175–1180 (2010).
Spillman, N. J. et al. Na+ Regulation in the Malaria Parasite Plasmodium falciparum Involves the Cation ATPase PfATP4 and Is a Target of the Spiroindolone Antimalarials. Cell Host Microbe 13, 227–237 (2013).
Rodrigues, T., Reker, D., Schneider, P. & Schneider, G. Counting on natural products for drug design. Nat. Chem. 8, 531–541 (2016).
Atanasov, A. G. et al. Natural products in drug discovery: advances and opportunities. Nat. Rev. Drug Discov. 20, 200–216 (2021).
Arnold, M. S. J. et al. Antiplasmodial activity of the natural product compounds alstonine and himbeline. Int. J. Parasitology: Drugs Drug Resistance 16, 17–22 (2021).
Nonaka, M. et al. Screening of a library of traditional Chinese medicines to identify anti-malarial compounds and extracts. Malar. J. 17, 244 (2018).
Jin, Z., Ma, J., Zhu, G. & Zhang, H. Discovery of Novel Anti-cryptosporidial Activities From Natural Products by in vitro High-Throughput Phenotypic Screening. Front. Microbiol. 10, https://doi.org/10.3389/fmicb.2019.01999 (2019).
Kabir, M. H. B. et al. Identification of potent anti-Cryptosporidium new drug leads by screening traditional Chinese medicines. PLOS Neglected Tropical Dis 16, e0010947 (2022).
Adeyemi, O. S., Sugi, T., Han, Y. & Kato, K. Screening of chemical compound libraries identified new anti-Toxoplasma gondii agents. Parasitol. Res. 117, 355–363 (2018).
Jiang, T. et al. Identification of fungal natural products with potent inhibition in Toxoplasma gondii. Microbiol. Spectr 12, e04142–04123 (2024).
Saito, H., Murata, Y., Nonaka, M. & Kato, K. Screening of a library of traditional Chinese medicines to identify compounds and extracts which inhibit Toxoplasma gondii growth. J. Vet. Med Sci. 82, 184–187 (2020).
Mazzone, F. et al. In vitro Biological Activity of Natural Products from the Endophytic Fungus Paraboeremia selaginellae against Toxoplasma gondii. Antibiotics (Basel) 11, https://doi.org/10.3390/antibiotics11091176 (2022).
Abu Hawsah, M. et al. In vitro studies for the antiparasitic activities of Azadirachta indica extract. Food Sci. Technol. 43, https://doi.org/10.1590/fst.117122 (2023).
Al-Quraishy, S. et al. Rumex nervosus changed the oxidative status of chicken caecum infected with Eimeria tenella. J. King Saud. Univ. - Sci. 32, 2207–2211 (2020).
Al-Shaebi, E. et al. In vitro anti-eimeriosis and anthelmintic activities for Achillea fragrantissima. Arquivo Brasileiro de Medicina Veterinária e Zootecnia 75, https://doi.org/10.1590/1678-4162-13025 (2023).
Al-Otaibi, T. et al. Biological activities of Persea americana: in vitro and in vivo studies. Food Sci.Technol. 43, https://doi.org/10.1590/fst.123722 (2023).
Guo, J., Luo, X., Wang, S., He, L. & Zhao, J. Xanthohumol and Gossypol Are Promising Inhibitors against Babesia microti by in vitro Culture via High-Throughput Screening of 133 Natural Products. Vaccines 8, 613 (2020).
Li, Y. et al. Discovering the Potent Inhibitors Against Babesia bovis in vitro and Babesia microti in vivo by Repurposing the Natural Product Compounds. Front Vet. Sci. 8, 762107 (2021).
Ji, S. et al. In vitro screening of novel anti-Babesia gibsoni drugs from natural products. Parasitol. Int. 85, 102437 (2021).
Feng, Y. et al. A Systematic Meta-Analysis of Global Sarcocystis Infection in Sheep and Goats. Pathogens 12, https://doi.org/10.3390/pathogens12070902 (2023).
García, G. Á. Besnoitiosis in Animals, https://www.msdvetmanual.com/infectious-diseases/besnoitiosis/besnoitiosis-in-animals (2021).
Cragg, G. M., Schepartz, S. A., Suffness, M. & Grever, M. R. The Taxol Supply Crisis. New NCI Policies for Handling the Large-Scale Production of Novel Natural Product Anticancer and Anti-HIV Agents. J. Nat. Products 56, 1657–1668 (1993).
Singh, B. K. & Macdonald, C. A. Drug discovery from uncultivable microorganisms. Drug Discov. Today 15, 792–799 (2010).
Sharma, R., Ranjan, R., Kapardar, R. K. & Grover, A. Unculturable’ bacterial diversity: An untapped resource. Curr. Sci. 89, 72–77 (2005).
Miethke, M. et al. Towards the sustainable discovery and development of new antibiotics. Nat. Rev. Chem. 5, 726–749 (2021).
Kobrehel, G., Radobolja, G., Tamburasev, Z., & Djokic, S. 11-Aza-10-Deozo-10-Dihydroerythromycin A and Derivatives Thereof as Well as a Process for their Preparation. U.S. Patent. patent (1982).
Kobrehel, G., Djokic, S. 11-Methyl-11-Aza-4-O-Cladinosyl-6-O-Desosamynyl-15-Ethyl-7,13,14-Trihydroxy-3,5,7,9,12,14-Hexamethyloxacyclopentadecane-2-One and Derivatives Thereof. U.S. Patent. patent (1985).
Kunakom, S. & Eustáquio, A. S. Natural Products and Synthetic Biology: Where We Are and Where We Need To Go. mSystems 4, https://doi.org/10.1128/mSystems.00113-19 (2019).
Luo, X. et al. Complete biosynthesis of cannabinoids and their unnatural analogues in yeast. Nature 567, 123–126 (2019).
Hwang, S., Lee, N., Cho, S., Palsson, B. & Cho, B.-K. Repurposing Modular Polyketide Synthases and Non-ribosomal Peptide Synthetases for Novel Chemical Biosynthesis. Front. Molecular Biosci. 7, https://doi.org/10.3389/fmolb.2020.00087 (2020).
Grkovic, T. et al. National Cancer Institute (NCI) Program for Natural Products Discovery: Rapid Isolation and Identification of Biologically Active Natural Products from the NCI Prefractionated Library. ACS Chem. Biol. 15, 1104–1114 (2020).
Martínez-Fructuoso, L. et al. Screen for New Antimicrobial Natural Products from the NCI Program for Natural Product Discovery Prefractionated Extract Library. ACS Infect. Dis. 9, 1245–1256 (2023).
Thornburg, C. C. et al. NCI Program for Natural Product Discovery: A Publicly-Accessible Library of Natural Product Fractions for High-Throughput Screening. ACS Chem. Biol. 13, 2484–2497 (2018).
Hoffman, P. S. et al. Antiparasitic drug nitazoxanide inhibits the pyruvate oxidoreductases of Helicobacter pylori, selected anaerobic bacteria and parasites, and Campylobacter jejuni. Antimicrob. Agents Chemother. 51, 868–876 (2007).
Ashigbie, P. G. et al. Use-case scenarios for an anti-Cryptosporidium therapeutic. PLoS Negl. Trop. Dis. 15, e0009057 (2021).
Jain, V., Kikuchi, H., Oshima, Y., Sharma, A. & Yogavel, M. Structural and functional analysis of the anti-malarial drug target prolyl-tRNA synthetase. J. Struct. Funct. Genom. 15, 181–190 (2014).
Australian Pesticides & Veterinary Medicines Authority. Trade Advice Notice for Halocur oral solution for treatment of calves (APVMA Product Number 57163). (Australia, 2007).
De Stasio, E. A., Moazed, D., Noller, H. F. & Dahlberg, A. E. Mutations in 16S ribosomal RNA disrupt antibiotic–RNA interactions. Embo j. 8, 1213–1216 (1989).
Ferone, R., Burchall, J. J. & Hitchings, G. H. Plasmodium berghei Dihydrofolate Reductase Isolation, Properties, and Inhibition by Antifolates. Mol. Pharmacol. 5, 49–59 (1969).
Triglia, T., Menting, J. G., Wilson, C. & Cowman, A. F. Mutations in dihydropteroate synthase are responsible for sulfone and sulfonamide resistance in Plasmodium falciparum. Proc. Natl. Acad. Sci. USA 94, 13944–13949 (1997).
Noack, S., Chapman, H. D. & Selzer, P. M. Anticoccidial drugs of the livestock industry. Parasitol. Res. 118, 2009–2026 (2019).
James, S. Thiamine uptake in isolated schizonts of Eimeria tenella and the inhibitory effects of amprolium. Parasitology 80, 313–322 (1980).
Ariyibi, A. A., Odunuga, O. O. & Olorunsogo, O. O. Concentration-dependent inhibition of sheep erythrocyte ghost plasma membrane Ca2+-ATPase activity by Berenil. J. Vet. Pharm. Ther. 24, 233–236 (2001).
Patrick, D. A. et al. Anti-Pneumocystis carinii pneumonia activity of dicationic carbazoles. Eur. J. Med. Chem 32, 781–793 (1997).
Pilch, D. S., Kirolos, M. A., Liu, X., Plum, G. E. & Breslauer, K. J. Berenil [1,3-bis(4’-amidinophenyl)triazene] binding to DNA duplexes and to a RNA duplex: evidence for both intercalative and minor groove binding properties. Biochemistry 34, 9962–9976 (1995).
Silva, J. H. D. et al. Chemoprophylaxis for babesiosis and anaplasmosis in cattle: case report. Rev. Bras. Parasitol. Vet. 29, e010520 (2020).
Kuttler, K. L., Graham, O. H. & Trevino, J. L. The effect of Imidocarb treatment on Babesia in the bovine and the tick (Boophilus microplus)*. Res. Vet. Sci. 18, 198–200 (1975).
Fry, M. & Pudney, M. Site of action of the antimalarial hydroxynaphthoquinone, 2-[trans-4-(4’-chlorophenyl) cyclohexyl]-3-hydroxy-1,4-naphthoquinone (566C80). Biochem Pharm. 43, 1545–1553 (1992).
Srivastava, I. K., Rottenberg, H. & Vaidya, A. B. Atovaquone, a broad spectrum antiparasitic drug, collapses mitochondrial membrane potential in a malarial parasite. J. Biol. Chem. 272, 3961–3966 (1997).
Wong, W. et al. Mefloquine targets the Plasmodium falciparum 80S ribosome to inhibit protein synthesis. Nat. Microbiol 2, 17031 (2017).
Sheridan, C. M., Garcia, V. E., Ahyong, V. & DeRisi, J. L. The Plasmodium falciparum cytoplasmic translation apparatus: a promising therapeutic target not yet exploited by clinically approved anti-malarials. Malar. J. 17, 465 (2018).
Villacorta, I., Peeters, J. E., Vanopdenbosch, E., Ares-Mazás, E. & Theys, H. Efficacy of halofuginone lactate against Cryptosporidium parvum in calves. Antimicrob. Agents Chemother. 35, 283–287 (1991).
Kiltz, H. H. & Humke, R. Bovine theileriosis in Burundi: chemotherapy with halofuginone lactate. Trop.Anim. Health Prod. 18, 139–145 (1986).
Acknowledgements
This work was conducted as part of the Australian Research Council Industrial Transformation Training Centre for Environmental and Agricultural Solutions to Antimicrobial Resistance (IC220100050) and funded by its Partners and the Australian Government. Support was also received through the National Health and Medical Research Council of Australia (Project Grant 1143974 to D.W.W., Development Grant 1135421 to B.E.S). E.Y.M. was supported by an ARC-ITTC Scholarship, D.W.W. by a Hospital Research Foundation Fellowship (2019/41-83100). B.E.S. is a Corin Centenary Fellow.
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D.W.W., M.R.G., E.Y.M., conceived the idea of this review; E.Y.M. and S.W.P. conducted the literature review; E.Y.M. and D.W.W. wrote the manuscript with input from M.R.G, S.W.P. and B.E.S.; E.Y.M. prepared the figures. All authors contributed to the review and editing of this manuscript.
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Authors E.Y.M., B.E.S., M.R.G. and D.W.W. declare no financial or non-financial competing interests. Author S.W.P. holds shares in Advanced Veterinary Therapeutics, Luoda Pharma and Neoculi, and has previously acted as a paid consultant for Zoetis, Boehringer Ingleheim, Elanco, Virbac and Ceva but declares no financial or non-financial competing interests.
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Mao, E.Y., Page, S.W., Sleebs, B.E. et al. A review of natural products as a source of next-generation drugs against apicomplexan parasites. npj Antimicrob Resist 3, 51 (2025). https://doi.org/10.1038/s44259-025-00119-x
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DOI: https://doi.org/10.1038/s44259-025-00119-x
