New paper! An antibiotic from an uncultured bacterium binds to an immutable target
Antimicrobial resistance is a leading mortality factor worldwide. Here, we report the discovery of clovibactin, an antibiotic isolated from uncultured soil bacteria. Clovibactin efficiently kills drug-resistant Gram-positive bacterial pathogens without detectable resistance. Using biochemical assays, solid-state nuclear magnetic resonance, and atomic force microscopy, we dissect its mode of action. Clovibactin blocks cell wall synthesis by targeting pyrophosphate of multiple essential peptidoglycan precursors (C55PP, lipid II, and lipid IIIWTA). Clovibactin uses an unusual hydrophobic interface to tightly wrap around pyrophosphate but bypasses the variable structural elements of precursors, accounting for the lack of resistance. Selective and efficient target binding is achieved by the sequestration of precursors into supramolecular fibrils that only form on bacterial membranes that contain lipid-anchored pyrophosphate groups. This potent antibiotic holds the promise of enabling the design of improved therapeutics that kill bacterial pathogens without resistance development.
Congratulations to all authors!
Shukla R, Peoples AJ, Ludwig KC, Maity S, Derks MGN, De Benedetti S, Krueger AM, Vermeulen BJA, Harbig T, Lavore F, Kumar R, Honorato RV, Grein F, Nieselt K, Liu Y, Bonvin AMJJ, Baldus M, Kubitscheck U, Breukink E, Achorn C, Nitti A, Schwalen CJ, Spoering AL, Ling LL, Hughes D, Lelli M, Roos WH, Lewis K, Schneider T, Weingarth M.
Follow this link for full access to the paper: https://doi.org/10.1016/j.cell.2023.07.038