The role of chemical synthesis in developing RiPP antibiotics.

Sam M Rowe,David R Spring

doi:10.1039/d0cs01386b

Abstract

The growing antimicrobial resistance crisis necessitates the discovery and development of novel classes of antibiotics if a 'postantibiotic era' is to be avoided. Ribosomally synthesised and post-translationally modified peptides, or RiPPs, are becoming increasingly recognised as a potential source of antimicrobial drugs. This is due to a combination of their potent antimicrobial activity and their high stability relative to unmodified linear peptides. However, as peptide drugs, their clinical development is often perturbed by issues such as low solubility and poor bioavailability. Chemical synthesis has the potential to overcome some of these challenges. Furthermore, the structural complexity of RiPPs makes them interesting synthetic targets in their own right, with the total synthesis of some structural classes having only been recently realised. This review focusses on the use of RiPPs as antimicrobial agents and will highlight various strategies that have been employed to chemically synthesise three major classes of RiPPs: lasso peptides, cyclotides, and lanthipeptides.

Highlights

Diseases caused by pathogens exhibiting antimicrobial resistance (AMR) are currently responsible for 700 000 deaths a year globally
VanNieuwenhze and co-workers have used a similar orthogonal protection strategy to synthesise the D-ring of mersacidin, a methicillin-resistant S. aureus (MRSA) active lantibiotic, which contains a sensitive AviMeCys bridge (Fig. 4a), showing that the methodology can be extended beyond the typical Lan/MeLan bridge.[46]
This study demonstrates that the A2 peptide has two independent mechanisms of action and makes clear the role that chemical synthesis can play in understanding mechanisms of antimicrobial activity

Summary

Introduction

Diseases caused by pathogens exhibiting antimicrobial resistance (AMR) are currently responsible for 700 000 deaths a year globally. Fliss and co-workers have reported ‘folded’ but non-lasso derivates of MccJ25 that retain some bactericidal activity.[15] Tulla-Puche and co-workers have reported synthesis of a lasso-inspired peptide in which the tail was covalently attached to the macrolactam ring but does not pass through it.[16] The synthesis required the use of 10 different protecting groups, affording an unthreaded variant of chaxapeptin that displayed good thermal stability and protease resistance.

Results

Conclusion