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Publication Abstract from PubMed

Infections by Staphylococcus aureus have been treated historically with beta-lactam antibiotics. However, these antibiotics have become obsolete in methicillin-resistant S. aureus by acquisition of the bla and mec operons. The presence of the beta-lactam antibiotic is detected by the sensor domains of BlaR and/or MecR, and the information is transmitted to the cytoplasm, resulting in derepression of the antibiotic-resistance genes. We hypothesized that inhibition of the sensor domain would shut down this response system, and beta-lactam susceptibility would be restored. An in silico search of 11 million compounds led to a benzimidazole-based hit and, ultimately, to the boronate 4. The X-ray structure of 4 is covalently engaged with the active-site serine of BlaR. Compound 4 potentiates by 16- to 4,096-fold the activities of oxacillin and of meropenem against methicillin-resistant S. aureus strains. The combination of 4 with oxacillin or meropenem shows efficacy in infected mice, validating the strategy.

Restoring susceptibility to beta-lactam antibiotics in methicillin-resistant Staphylococcus aureus.,Nguyen VT, Birhanu BT, Miguel-Ruano V, Kim C, Batuecas M, Yang J, El-Araby AM, Jimenez-Faraco E, Schroeder VA, Alba A, Rana N, Sader S, Thomas CA, Feltzer R, Lee M, Fisher JF, Hermoso JA, Chang M, Mobashery S Nat Chem Biol. 2024 Jul 26. doi: 10.1038/s41589-024-01688-0. PMID:39060390^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.