WEHI Special ACRF Chemical Biology Seminar hosted by Dr Brad Sleebs
 

Wenyi Li

Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University

Using peptides to combat bacterial infections

Davis Auditorium

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Including Q&A session

Since the discovery of penicillin and subsequent antibiotics, the increasing global consumption and inappropriate use of these ‘wonder’ drugs has played a critical role in driving antimicrobial resistance (AMR) in the last two decades at an alarming rate as assessed by World Health Organization (WHO)[1]. Antimicrobial peptides (AMPs), known as host defence peptides, are potentially potent alternatives to conventional antibiotics given their broad spectrum of activity[2-5]. They mainly interact with cell membranes through surface electrostatic potentials and the formation of secondary structures, resulting in permeability and destruction of target microorganism membranes [6].

To further improve the antibacterial activity, we have applied different chemical modifications on several AMPs, including multimerization, conjugation and lipidation. For example, we used a series of bifunctional linkers to multimerise AMPs from their linear monomeric form containing a C-terminal hydrazide to either a discontinuous dimer or tetramer[7-8]. Additionally, the attachment of moderate-length lipid carbon chains to cationic peptides can assist peptide inserts into the membrane lipid bilayer, inducing curvature and resulting in membrane pore formation, destabilization, depolarization, and leakage[9]. Thus, we modified a series of AMPs by adding lipids of various sizes and then evaluated their antibacterial activity and conducted mechanistic investigations to characterize their aggregation tendency[10]. Our findings highlight the advantages of modern chemical biology methods to develop novel AMPs having both more potent and broad spectrum antibacterial activity.

References

1.         S. C. Roberts, T. R. Zembower, Lancet Infect Dis 2020, 21, 10-11.

2.         W. Li, F. Separovic, N. M. O’Brien-Simpson, J. D. Wade, Chem. Soc. Rev. 2021, 50, 4932-4973.

3.         B. Lin, A. Hung, R. Li, A. Barlow, W. Singleton, T. Matthyssen, M.-A. Sani, M. A. Hossain, J. D. Wade, N. M. O’Brien- Simpson, W. Li, Eur. J. Med. Chem. 2022, 231, 114135.

4.         B. Lin, R. Li, T. N. G. Handley, J. D. Wade, W. Li, N. M. O’Brien-Simpson, ACS Infect. Dis. 2021, 7, 2959–2970.

5.         P. Chen, T. Ye, C. Li, P. Praveen, Z. Hu, W. Li, C. Shang, Nat. Prod. Rep. 2023.

6.         J. Koehbach, D. J. Craik, Trends Pharmacol. Sci. 2019, 40, 517-528.

7.         W. Li, N. M. O’Brien-Simpson, S. Yao, J. Tailhades, E. C. Reynolds, R. M. Dawson, L. Otvos, M. A. Hossain, F. Separovic, J. D. Wade, Chem. Eur. J. 2017, 23, 390-396.

8.         W. Li, F. Lin, A. Hung, A. Barlow, M.-A. Sani, R. Paolini, W. Singleton, J. Holden, M. A. Hossain, F. Separovic, N. M. O’Brien-Simpson, J. D. Wade, Chem. Sci. 2022, 13, 2226-2237.

9.         S. Nasompag, P. Dechsiri, N. Hongsing, P. Phonimdaeng, S. Daduang, S. Klaynongsruang, T. A. Camesano, R. Patramanon, Biochim. Biophys. Acta, Biomembr. 2015, 1848, 2351-2364.

10.       B. Lin, A. Hung, W. Singleton, K. K. Darmawan, R. Moses, B. Yao, H. Wu, A. Barlow, M.-A. Sani, A. J. Sloan, M. A. Hossain, J. D. Wade, Y. Hong, N. M. O’Brien-Simpson, W. Li, Aggregate 2023, e329

All welcome!