A new antibiotic from an uncultured bacterium binds to an immutable target.
Rhythm ShuklaAaron J PeoplesKevin C LudwigSourav MaityMaik G N DerksStefania de BenedettiAnnika M KruegerBram J A VermeulenFrancesca LavoreRodrigo V HonoratoFabian GreinAlexandre BonvinUlrich KubitscheckEefjan BreukinkCatherine AchornAnthony NittiChristopher J SchwalenAmy L SpoeringLosee Lucy LingDallas HughesMoreno LelliWouter H RoosKim LewisTanja SchneiderMarkus H WeingarthPublished in: bioRxiv : the preprint server for biology (2023)
Antimicrobial resistance is a leading mortality factor worldwide. Here we report the discovery of clovibactin, a new antibiotic, isolated from uncultured soil bacteria. Clovibactin efficiently kills drug-resistant bacterial pathogens without detectable resistance. Using biochemical assays, solid-state NMR, and atomic force microscopy, we dissect its mode of action. Clovibactin blocks cell wall synthesis by targeting pyrophosphate of multiple essential peptidoglycan precursors (C 55 PP, Lipid II, Lipid WTA ). 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 irreversible sequestration of precursors into supramolecular fibrils that only form on bacterial membranes that contain lipid-anchored pyrophosphate groups. Uncultured bacteria offer a rich reservoir of antibiotics with new mechanisms of action that could replenish the antimicrobial discovery pipeline.
Keyphrases
- antimicrobial resistance
- drug resistant
- solid state
- cell wall
- atomic force microscopy
- multidrug resistant
- high throughput
- acinetobacter baumannii
- small molecule
- fatty acid
- high speed
- magnetic resonance
- staphylococcus aureus
- gram negative
- high resolution
- cardiovascular events
- coronary artery disease
- pseudomonas aeruginosa
- dna binding
- single cell
- bacillus subtilis
- cystic fibrosis
- binding protein