The Dual Mode of Antibacterial Action of the Synthetic Small Molecule DCAP Involves Lipid II Binding.
Kevin Christopher LudwigJan-Samuel PulsCruz L Matos de OpitzPaolo InnocentiJan-Martin DanielJan BornikoelMelina ArtsSebastian KrannichJan StraetenerDominik BrajtenbachBeate HenrichfreisePeter SassAnna MuellerNathaniel I MartinHeike Brötz-OesterheltUlrich KubitscheckFabian GreinTanja SchneiderPublished in: Journal of the American Chemical Society (2024)
The synthetic small molecule DCAP is a chemically well-characterized compound with antibiotic activity against Gram-positive and Gram-negative bacteria, including drug-resistant pathogens. Until now, its mechanism of action was proposed to rely exclusively on targeting the bacterial membrane, thereby causing membrane depolarization, and increasing membrane permeability (Eun et al. 2012, J. Am. Chem. Soc. 134 (28), 11322-11325; Hurley et al. 2015, ACS Med. Chem. Lett. 6, 466-471). Here, we show that the antibiotic activity of DCAP results from a dual mode of action that is more targeted and multifaceted than previously anticipated. Using microbiological and biochemical assays in combination with fluorescence microscopy, we provide evidence that DCAP interacts with undecaprenyl pyrophosphate-coupled cell envelope precursors, thereby blocking peptidoglycan biosynthesis and impairing cell division site organization. Our work discloses a concise model for the mode of action of DCAP which involves the binding to a specific target molecule to exert pleiotropic effects on cell wall biosynthetic and divisome machineries.
Keyphrases
- small molecule
- cell wall
- drug resistant
- multidrug resistant
- gram negative
- single cell
- acinetobacter baumannii
- single molecule
- high throughput
- cell therapy
- protein protein
- cancer therapy
- acute coronary syndrome
- stem cells
- binding protein
- optical coherence tomography
- pseudomonas aeruginosa
- mesenchymal stem cells
- quantum dots
- cystic fibrosis
- dna binding