UBC Theses and Dissertations
Role of aspartate aminotransferases AspB and AspC in the WhiB7-controlled intrinsic drug resistance system of mycobacteria Ng, Carol Ka Lo
Intrinsic resistance of the intracellular pathogen Mycobacterium tuberculosis is one of the main reasons that the disease tuberculosis is difficult to treat and why it remains as one of the world’s most prevalent and dangerous infectious diseases. The intrinsic resistance regulator WhiB7 controls a regulon that contains many genes predicted to have physiological functions including aspartate aminotransferases, aspB and aspC. Multi-drug susceptibility was observed in an aspC mutant and an aspB constitutive expression strain. The expression of aspC was positively regulated by WhiB7 while expression of aspB downregulated whiB7 expression. The fitness of Mycobacterium smegmatis was affected negatively by oxaloacetate and positively by α-ketoglutarate, substrates of aspartate aminotransferase, which then altered the growth inhibition by antibiotics. Recombinant AspB and AspC both catalyze measurable transamination of aspartate and α-ketoglutarate. AspC plays an important role in mycobacteria physiology as deletion of this gene caused many growth deficiencies. Furthermore, the physiological role of AspC extended beyond amino acid intermediary metabolism to redox homeostasis and oxidative stress detoxification. These results revealed a link between intrinsic antibiotic resistance and metabolism mediated through AspB and AspC. Since antibiotic resistance in mycobacterium is a complex function of its physiology, it is important to screen for tuberculosis drugs under growth conditions that resemble those found in vivo.
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