Mutations in fbiD (Rv2983) as a novel determinant of resistance to pretomanid and delamanid in Mycobacterium tuberculosis
| Autor: | Thomas R. Ioerger, Jin Lee, Keshav Shah, Jean Philippe Lanoix, Dalin Rifat, Ghader Bashiri, Eric L. Nuermberger, James C. Sacchettini, Si-Yang Li |
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| Rok vydání: | 2020 |
| Předmět: |
Tuberculosis
medicine.drug_class Mutant Antibiotics Antitubercular Agents Microbiology Mycobacterium tuberculosis 03 medical and health sciences Mice chemistry.chemical_compound Mechanisms of Resistance medicine Animals Pharmacology (medical) Oxazoles Gene 030304 developmental biology Pharmacology 0303 health sciences Nitroimidazole biology 030306 microbiology medicine.disease biology.organism_classification Infectious Diseases chemistry Nitroimidazoles Pretomanid Mutation Delamanid medicine.drug |
| Zdroj: | Antimicrob Agents Chemother |
| Popis: | The nitroimidazole pro-drugs delamanid and pretomanid comprise one of only two new antimicrobial classes approved to treat tuberculosis (TB) in 50 years. Prior in vitro studies suggest a relatively low barrier to nitroimidazole resistance in Mycobacterium tuberculosis, but clinical evidence is limited to date. We selected pretomanid-resistant M. tuberculosis mutants in two mouse models of TB using a range of pretomanid doses. The frequency of spontaneous resistance was approximately 10−5 CFU. Whole genome sequencing of 161 resistant isolates from 47 mice revealed 99 unique mutations, 91% of which occurred in 1 of 5 genes previously associated with nitroimidazole activation and resistance: fbiC (56%), fbiA (15%), ddn (12%), fgd (4%) and fbiB (4%). Nearly all mutations were unique to a single mouse and not previously identified. The remaining 9% of resistant mutants harbored mutations in Rv2983, a gene not previously associated with nitroimidazole resistance but recently shown to be a guanylyltransferase necessary for cofactor F420 synthesis. Most mutants exhibited high-level resistance to pretomanid and delamanid, although Rv2983 and fbiB mutants exhibited high-level pretomanid resistance, but relatively small changes in delamanid susceptibility. Complementing an Rv2983 mutant with wild-type Rv2983 restored susceptibility to pretomanid and delamanid. By quantifying intracellular F420 and its precursor Fo in overexpressing and loss-of-function mutants, we provide further evidence that Rv2983 is necessary for F420 biosynthesis. Finally, Rv2983 mutants and other F420H2-deficient mutants displayed hypersusceptibility to some antibiotics and to concentrations of malachite green found in solid media used to isolate and propagate mycobacteria from clinical samples. |
| Databáze: | OpenAIRE |
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