1. Dimeric Stilbene Antibiotics Target the Bacterial Cell Wall in Drug-Resistant Gram-Positive Pathogens.
- Author
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Goddard TN, Patel J, Park HB, and Crawford JM
- Subjects
- Anti-Bacterial Agents chemistry, Humans, Methicillin pharmacology, Microbial Sensitivity Tests, Molecular Structure, Stilbenes chemistry, Vancomycin pharmacology, Anti-Bacterial Agents pharmacology, Cell Wall drug effects, Drug Resistance, Bacterial drug effects, Enterococcus faecium cytology, Enterococcus faecium drug effects, Methicillin-Resistant Staphylococcus aureus cytology, Methicillin-Resistant Staphylococcus aureus drug effects, Stilbenes pharmacology
- Abstract
The prevalence of antibiotic resistance has been increasing globally, and new antimicrobial agents are needed to address this growing problem. We previously reported that a stilbene dimer from Photorhabdus gammaproteobacteria exhibits strong activity relative to its monomer against the multidrug-resistant Gram-positive pathogens methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis . Here, we show that related dietary plant stilbene-derived dimers also have activity against these pathogens, and MRSA is unable to develop substantial resistance even after daily nonlethal exposure to the lead compound for a duration of three months. Through a systematic deduction process, we established the mode of action of the lead dimer, which targets the bacterial cell wall. Genome sequencing of modest resistance mutants, mass spectrometry analysis of cell wall precursors, and exogenous lipid II chemical complementation studies support the target as being lipid II itself or lipid II trafficking processes. Given the broad distribution of stilbenes in plants, including dietary plants, we anticipate that our mode of action studies here could be more broadly applicable to multipartite host-bacterium-plant interactions.
- Published
- 2020
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