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Dimeric Stilbene Antibiotics Target the Bacterial Cell Wall in Drug-Resistant Gram-Positive Pathogens
journal contribution
posted on 2020-05-21, 15:54 authored by Tyler
N. Goddard, Jaymin Patel, Hyun Bong Park, Jason M. CrawfordThe
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.
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genome sequencinglipid IImass spectrometry analysisdeduction processmodePhotorhabdus gammaproteobacteria exhibitsantimicrobial agentsvancomycin-resistant Enterococcus faecalisDimeric Stilbene Antibiotics Targetexogenous lipid II chemical complementation studies supportplant stilbene-derived dimerslipid II trafficking processesresistance mutantscell wall precursorscell wallDrug-Resistant Gram-Positive PathogensMRSABacterial Cell Wallstilbene dimermultidrug-resistant Gram-positive pathogens methicillin-resistant Staphylococcus aureusantibiotic resistanceaction studies
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