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Antimicrobial activity of α/β hybrid peptides incorporating tBu-β3,3Ac6c against methicillin-resistant Staphylococcus aureus

The Journal of Antibiotics volume 77, pages 794–801 (2024)Cite this article

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Abstract

The incorporation of β-amino acids into peptides is a promising approach to develop proteolytically stable therapeutic agents. Short α/β hybrid peptides containing tBu-β3,3Ac6cː H2N-Lys-tBu-β3,3Ac6c-PEA, P1; H2N-Orn-tBu-β3,3Ac6c-PEA, P2; H2N-Arg-tBu-β3,3Ac6c-PEA, P3; LA-Lys-tBu-β3,3Ac6c-PEA, P4; LA-Orn-tBu-β3,3Ac6c-PEA, P5; LA-Arg-tBu-β3,3Ac6c-PEA, P6; LAu-Lys-tBu-β3,3Ac6c-PEA, P7; LAu-Orn-tBu-β3,3Ac6c-PEA, P8; and LAu-Arg-tBu-β3,3Ac6c-PEA, P9 were prepared. The antimicrobial efficacies of all the peptides were evaluated against ESKAPE pathogens, along with a small panel of multi-drug resistant (MDR) clinical isolates of S. aureus. Among all the peptides, P4, P6, and P7 showed significant efficacies against P. aeruginosa, S. aureus, and MRSA with an MIC value ranging from 6.25 to 12.5 μM. Further, in vitro, anti-staphylococcal assessment with their antimicrobial synergy of the peptides P4, P6, and P7 was carried out against MRSA, due to its better efficacy. The peptides P6 and P7 exhibited MRSA biofilm inhibition of 70% and 77%, respectively, at 4×MIC concentration. At its MIC concentration, about 19% hemolysis was observed for P4, P6, and P7.

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References

  1. Santajit S, Indrawattana N. Mechanisms of antimicrobial resistance in ESKAPE pathogens: BioMed Research International, 2016;2475067.

  2. Aslam B, Aslam B, Wang W, Arshad MI, Khurshid M, Muzammil S, Rasool MH, Nisar MA, Alvi RF, Aslam MA, Qamar MU, Salamat MKF. Antibiotic resistance: a rundown of a global crisis. Infect Drug Resist. 2018;11:1645–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Huan Y, Kong Q, Mou H, Yi H. Antimicrobial peptides: classification, design, application and research progress in multiple fields. Front Microbiol. 2020;11:582779.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Hicks RP, Bhonsle JB, Venugopal D, Koser BW, Magill AJ. De novo design of selective antibiotic peptides by incorporation of unnatural amino acids. J Med Chem. 2007;50:3026–36.

    Article  CAS  PubMed  Google Scholar 

  5. Gentilucci L, De Marco R, Cerisoli L. Chemical modifications designed to improve peptide stability: incorporation of non-natural amino acids, pseudo-peptide bonds, and cyclization. Curr Pharm Des. 2010;16:3185–203.

    Article  CAS  PubMed  Google Scholar 

  6. Cabrele C, Martinek TA, Reiser O, Berlicki Ł. Peptides containing β-amino acid patterns: challenges and successes in medicinal chemistry. J Med Chem. 2014;57:9718–39.

    Article  CAS  PubMed  Google Scholar 

  7. Wani NA, Singh G, Shankar S, Sharma A, Katoch M, Rai R. Short hybrid peptides incorporating β-and γ-amino acids as antimicrobial agents. Peptides. 2017;97:46–53.

    Article  CAS  PubMed  Google Scholar 

  8. Shankar SS, Benke SN, Nagendra N, Srivastava PL, Thulasiram HV, Gopi HN. Self-assembly to function: design, synthesis, and broad spectrum antimicrobial properties of short hybrid E-vinylogous lipopeptides. J Med Chem. 2013;56:8468–74.

    Article  CAS  PubMed  Google Scholar 

  9. Benke SN, Thulasiram HV, Gopi HN. Potent antimicrobial activity of lipidated short α, γ‐hybrid peptides. ChemMedChem. 2017;12:1610–5.

    Article  CAS  PubMed  Google Scholar 

  10. Aguilar M-I, Purcell AW, Devi R, Lew R, Rossjohn J, Smith AI, Perlmutter P. β-Amino acid-containing hybrid peptides—new opportunities in peptidomimetics. Org Biomol Chem. 2007;5:2884–90.

    Article  CAS  PubMed  Google Scholar 

  11. Schmitt MA, Weisblum B, Gellman SH. Interplay among folding, sequence, and lipophilicity in the antibacterial and hemolytic activities of α/β-peptides. J Am Chem Soc. 2007;129:417–28.

    Article  CAS  PubMed  Google Scholar 

  12. Chowdhary R, Mubarak MM, Kantroo HA, ur Rahim J, Malik A, Sarkar AR, Bashir G, Ahmad Z, Rai R. Synthesis, characterization, and antimicrobial activity of ultra-short cationic β-peptides. ACS Infect Dis. 2023;9:1437–48.

    Article  CAS  PubMed  Google Scholar 

  13. Schmitt MA, Weisblum B, Gellman SH. Unexpected relationships between structure and function in α, β-peptides: antimicrobial foldamers with heterogeneous backbones. J Am Chem Soc. 2004;126:6848–9.

    Article  CAS  PubMed  Google Scholar 

  14. Vestergaard M, Skive B, Domraceva I, Ingmer H, Franzyk H. Peptide/β-peptoid hybrids with activity against vancomycin-resistant enterococci: influence of hydrophobicity and structural features on antibacterial and hemolytic properties. Int J Mol Sci. 2021;22:5617.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ur Rahim J, Singh G, Shankar S, Katoch M, Rai R. Tetrahydropiperic acid (THPA) conjugated cationic hybrid dipeptides as antimicrobial agents. J Antibiot. 2021;74:480–3.

    Article  CAS  Google Scholar 

  16. Shankar S, Jyothi D, Rahim JU, Pal PC, Singh UP, Rai R. Conformation of achiral α/β hybrid peptides containing glycine and 1‐aminocyclohexaneacetic acid: ChemistrySelect. 2022;7:e202104453.

  17. Lehto T, Vasconcelos L, Margus H, Figueroa R, Pooga M, Hällbrink M, Langel U. Saturated fatty acid analogues of cell-penetrating peptide PepFect14: role of fatty acid modification in complexation and delivery of splice-correcting oligonucleotides. Bioconjugate Chem. 2017;28:782–92.

    Article  CAS  Google Scholar 

  18. Violette A, Fournel S, Lamour K, Chaloin O, Frisch B, Briand JP, Guichard G. Mimicking helical antibacterial peptides with nonpeptidic folding oligomers. Chem Biol. 2006;13:531–8.

    Article  CAS  PubMed  Google Scholar 

  19. Kavaliauskas P, Acevedo W, Garcia A, Naing E, Grybaite B, Sapijanskaite-Banevic B, Grigaleviciute R, Petraitiene R, Mickevicius V, Petraitis V. Exploring the potential of bis (thiazol-5-yl) phenylmethane derivatives as novel candidates against genetically defined multidrug-resistant Staphylococcus aureus. Plos one. 2024;19:e0300380.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Oliveira W, Silva PMS, Silva RCS, Silva GMM, Machado G, Coelho LCBB, Correia MTS. Staphylococcus aureus and Staphylococcus epidermidis infections on implants. J Hospital Infect. 2018;98:111–7.

    Article  CAS  Google Scholar 

  21. Bhattacharya M, Wozniak DJ, Stoodley P, Hall-Stoodley L. Prevention and treatment of Staphylococcus aureus biofilms. Expert Rev Anti Infect Ther. 2015;13:1499–516.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lister JL, Horswill AR. Staphylococcus aureus biofilms: recent developments in biofilm dispersal. Front Cell Infect Microbiol. 2014;4:178.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors are grateful to the Director, CSIR-IIIM, Jammu, for providing laboratory facilities to conduct this research. The work was supported by the internal institutional grant (MLP-110011) and (IIRP-0715/2023) from the Council of Scientific and Industrial Research (CSIR) and the Indian Council for Medical Research (ICMR) Government of India. ARS and RM thanks CSIR-IIIM for providing the project fellowship. JK and RC thank the Council of Scientific and Industrial Research (CSIR), India, for providing the fellowship. AR and SF thank the University Grant Commission (UGC), India, for providing the fellowship. The institutional publication number of the article is CSIR-IIIM/IPR/00727.

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  1. These authors contributed equally: Aminur Rahman Sarkar, Jyoti Kumari

Authors and Affiliations

  1. Natural Products and Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, Jammu and Kashmir, India

    Aminur Rahman Sarkar, Rubina Chowdhary & Rajkishor Rai

  2. Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, 201002, Uttar Pradesh, India

    Aminur Rahman Sarkar, Jyoti Kumari, Arti Rathore, Rubina Chowdhary, Shifa Firdous, Avisek Mahapa & Rajkishor Rai

  3. Infectious Diseases Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, Jammu and Kashmir, India

    Jyoti Kumari, Arti Rathore, Rakshit Manhas, Shifa Firdous & Avisek Mahapa

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Sarkar, A.R., Kumari, J., Rathore, A. et al. Antimicrobial activity of α/β hybrid peptides incorporating tBu-β3,3Ac6c against methicillin-resistant Staphylococcus aureus. J Antibiot 77, 794–801 (2024). https://doi.org/10.1038/s41429-024-00773-9

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