Fighting Antibiotic Resistant Tuberculosis: Structural Studies of an Mmpl

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Widespread use of antibiotics has driven evolution of resistance mechanisms in many pathogenic bacteria, approaching levels that warrant global health crisis status. Of notable concern is the emergence of multi-, extremely and totally-drug resistant strains of M.tuberculosis-the aetiological agent of tuberculosis (TB) disease and the leading cause of infectious disease-associated mortality worldwide. The situation has been further compounded by insufficient discovery of novel antituberculars, as well as an incomplete understanding of the mechanisms by which resistance is achieved at the molecular level. Spearheading part of an international anti-TB response, the Oxford-based CRyPTIC initiative is using whole-genome sequencing of >100,000 TB isolates to catalogue resistance mutations in both known and novel antitubercular targets. In collaboration with CRyPTIC, this project aims to use a combination of structural biology, functional biochemistry and computational approaches to begin combatting antibiotic resistant TB. Initial efforts will focus on the structural and functional characterisation of M.tuberculosis membrane proteins-alongside closely related C.glutamicum homologues-functioning in cellwall biosynthesis (the glycolipid transporters MmpL3, CmpL1 & CmpL3) or drug-efflux (MmpL5 & NCgl-1194). Both classes of protein have been implicated in antitubercular resistance and/or are required for M.tuberculosisviability; thus representing putative targets against which new antibiotics could be developed. Applying similar methodology, alongside complementary in silico free-energy calculations, a mechanistic understanding of how CRyPTIC-identified mutations in KatG (a catalase-peroxidase) are able to promote resistance to the front-line antitubercular isoniazid (INH) will also be sought. As the project progresses, new proteins implicated in resistance by CRyPTIC will be additionally investigated.BBSRC Priority Area: Combatting Antimicrobial Resistance; BfH, ENWW