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Drug Discovery

New class of antibiotics identified

Synthetic retinoids kill methicillin-resistant Staph infections and persisters associated with chronic infections

by Celia Henry Arnaud
April 2, 2018 | APPEARED IN VOLUME 96, ISSUE 14

Researchers have discovered a new class of potential antibiotics that work against methicillin-resistant Staphylococcus aureus (MRSA) and against so-called persisters, dormant bacteria associated with chronic infections (Nature 2018, DOI: 10.1038/nature26157). The team, led by Eleftherios Mylonakis of Brown University, Rhode Island Hospital, and Miriam Hospital, screened a library of small molecules to find ones that decrease MRSA’s ability to kill Caenorhabditis elegans, a model organism. From this screen, the researchers identified two synthetic retinoids known as CD437 and CD1530 as potential antibacterial compounds. When incubated with those compounds for two hours, the MRSA strain MW2 dropped below the limit of detection. When the researchers exposed the bacteria to elevated retinoid concentrations, they did not find any MW2 that had mutated to survive the treatments. And after 100 days of growing MW2 in doses of CD437 below the compound’s minimum inhibitory concentration, the researchers identified mutants with only a twofold increase in resistance, compared with a 256-fold increase in resistance to a standard antibiotic, ciprofloxacin, after 100 days. The retinoids were able, on their own or in combination with the antibiotic gentamicin, to kill growing and persister MRSA cells. The researchers found that the retinoids disrupt the bacterial membrane lipid bilayers and suspect that this damage increases gentamicin’s diffusion into the cells. In addition, the team developed an analog of CD437 that retains its ability to kill persisters while being less toxic to mammalian cells.



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