Antimicrobial Strategies for Gram-Negative Bacterial Infections

Gram-negative pathogens present a major clinical challenge owing to their dual-membrane envelope, which restricts drug uptake, and a versatile arsenal of resistance mechanisms including β-lactamase production, porin modifications and efflux pump overexpression. Traditional approaches such as carbapenems and extended-spectrum cephalosporins have been undermined by the rapid spread of carbapenemases and metallo-β-lactamases. In response, contemporary strategies encompass novel β-lactam/β-lactamase inhibitor combinations, siderophore-conjugated antibiotics that hijack iron‐uptake pathways, and adjunctive therapies that restore or potentiate existing agents. Beyond small molecules, research has advanced antimicrobial peptides, phage therapy and immunomodulatory agents to breach bacterial defences. Rational drug design guided by structural analyses of penicillin-binding proteins has yielded cephalosporins with enhanced affinity for key transpeptidases. Combination regimens pairing antibiotics with metal-based adjuvants or efflux pump inhibitors have shown promise in suppressing resistance emergence. Complementary approaches target quorum sensing or biofilm integrity to render bacteria more susceptible to host immunity and antimicrobials. Taken together, these innovations deliver a multipronged framework aimed at preserving efficacy, prolonging the life span of last-resort agents and providing practical options for treatment of multidrug-resistant Gram-negative infections worldwide.

Research from Nature Portfolio

Recent studies have unveiled the potential of metallo-sideromycin complexes to extend the utility of siderophore-antibiotics. In murine models of acute pneumonia, co-administration of a bismuth salt with a clinically approved siderophore-cephalosporin markedly reduced bacterial burden and improved survival. Mechanistically, the bismuth ion competes with iron at the antibiotic’s chelation site, increasing uptake of the metallo-drug while depleting intracellular iron and suppressing resistance development in Pseudomonas aeruginosa and related species. This co-therapy approach exemplifies how metal-based adjuvants can synergise with existing agents to overcome emerging resistance and underscores the translational potential of dual-function complexes.

Antimicrobial Strategies for Gram-Negative Bacterial Infections publication trend

The graph below shows the total number of articles in antimicrobial strategies for gram-negative bacterial infections across all publications each year (not limited to Nature Index journals).

Technical terms

Siderophore: Small molecule that chelates iron, exploited by bacteria for uptake and by certain antibiotics for cell entry.

β-lactamase: Enzyme that hydrolyses the β-lactam ring of antibiotics, neutralising their bactericidal action.

Porin: Outer membrane channel that permits diffusion of hydrophilic molecules into Gram-negative bacteria.

Efflux pump: Membrane protein complex that actively transports antimicrobial agents out of bacterial cells.

Carbapenem-resistant: Bacteria that have acquired mechanisms, often β-lactamases, rendering carbapenems ineffective.

Penicillin-binding protein 3 (PBP3): Transpeptidase enzyme essential for cell wall synthesis and a target for β-lactam antibiotics.

Heteroresistance: Phenomenon where subpopulations within a bacterial isolate display varied antibiotic susceptibilities.

References

1. Metallo-sideromycin as a dual functional complex for combating antimicrobial resistance. Nature Communications (2023).
2. Global prevalence of cefiderocol non-susceptibility in Enterobacterales, Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia: a systematic review and meta-analysis. Clinical Microbiology and Infection (2023).
3. Structural basis of Pseudomonas aeruginosa penicillin binding protein 3 inhibition by the siderophore-antibiotic cefiderocol. Chemical Science (2024).
4. Cefiderocol: Systematic Review of Mechanisms of Resistance, Heteroresistance and In Vivo Emergence of Resistance. Antibiotics (2022).