| Summary: | 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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