A new dehydratase conferring innate resistance to thiacetazone and intra-amoebal survival of Mycobacterium smegmatis

Molecular Microbiology
Séverine Carrère-KremerLaurent Kremer

Abstract

Nontuberculous mycobacteria are innately resistant to most antibiotics, although the mechanisms responsible for their drug resistance remain poorly understood. They are particularly refractory to thiacetazone (TAC), a second-line antitubercular drug. Herein, we identified MSMEG_6754 as essential for the innate resistance of Mycobacterium smegmatis to TAC. Transposon-mediated and targeted disruption of MSMEG_6754 resulted in hypersusceptibility to TAC. Conversely, introduction of MSMEG_6754 into Mycobacterium tuberculosis increased resistance 100-fold. Resolution of the crystal structure of MSMEG_6754 revealed a homodimer in which each monomer comprises two hot-dog domains characteristic of dehydratase-like proteins and very similar to the HadAB complex involved in mycolic acid biosynthesis. Gene inactivation of the essential hadB dehydratase could be achieved in M. smegmatis and M. tuberculosis only when the strains carried an integrated copy of MSMEG_6754, supporting the idea that MSMEG_6754 and HadB share redundant dehydratase activity. Using M. smegmatis-Acanthamoeba co-cultures, we found that intra-amoebal growth of the MSMEG_6754 deleted strain was significantly reduced compared with the parental strain. This in vivo growt...Continue Reading

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Citations

Jul 3, 2015·Molecular Microbiology·Vijayashankar NatarajApoorva Bhatt
Jul 8, 2016·Proceedings of the National Academy of Sciences of the United States of America·Iman HalloumLaurent Kremer
Jul 31, 2016·The Journal of Biological Chemistry·Maikel BootWilbert Bitter
Feb 29, 2020·The Journal of Biological Chemistry·Lin ShenChristophe Mariller
Apr 4, 2021·International Journal of Molecular Sciences·Jan MadackiJana Korduláková
Apr 11, 2018·Drug Discovery Today·Mu-Lu WuThomas Dick

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