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• W4300690561 abstract "Contezolid (MRX-I), a safer antibiotic of the oxazolidinone class, is a promising new antibiotic with potent activity against Mycobacterium tuberculosis (MTB) both in vitro and in vivo. To identify resistance mechanisms of contezolid in MTB, we isolated several in vitro spontaneous contezolid-resistant MTB mutants, which exhibited 16-fold increases in the MIC of contezolid compared with the parent strain but were still unexpectedly susceptible to linezolid. Whole-genome sequencing revealed that most of the contezolid-resistant mutants bore mutations in the mce3R gene, which encodes a transcriptional repressor. The mutations in mce3R led to markedly increased expression of a monooxygenase encoding gene Rv1936. We then characterized Rv1936 as a putative flavin-dependent monooxygenase that catalyzes the degradation of contezolid into its inactive 2,3-dihydropyridin-4-one (DHPO) ring-opened metabolites, thereby conferring drug resistance. While contezolid is an attractive drug candidate with potent antimycobacterial activity and low toxicity, the occurrence of mutations in Mce3R should be considered when designing combination therapy using contezolid for treating tuberculosis." @default.
• W4300690561 created "2022-10-04" @default.
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• W4300690561 date "2022-10-18" @default.
• W4300690561 modified "2023-10-14" @default.
• W4300690561 title "Drug Degradation Caused by <i>mce3R</i> Mutations Confers Contezolid (MRX-I) Resistance in Mycobacterium tuberculosis" @default.
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• W4300690561 doi "https://doi.org/10.1128/aac.01034-22" @default.
• W4300690561 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/36190243" @default.
• W4300690561 hasPublicationYear "2022" @default.
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