Targeting Mycobacterium tuberculosis intrinsic resistance mechanisms to potentiate antitubercular drug action

Abstract

The work presented herein has focused on understanding the mycobacterial metabolic responses that contribute to intrinsic resistance to the antitubercular drugs p-aminosalicylic acid and pyrazinamide. The interrogation of these responses has led to improved understanding of the underlying mechanisms conferring intrinsic resistance to each drug. Leveraging our observations, we were able to improve the antitubercular action of p-aminosalicylic acid by several orders of magnitude as well as circumvent a known mechanism of resistance. Further, we were able to decipher the long observed, but unknown mechanism responsible for conditional pyrazinamide susceptibility. Finally, we developed a method to drive pyrazinamide susceptibility in M. tuberculosis through co-treatment with peptidoglycan targeting drugs. These studies deepen our understanding of how M. tuberculosis withstands drug treatment and offers novel strategies to improve our ability to combat the disease.