Molecular Basis for Drug Susceptibility and Resistance in Mycobacterium tuberculosis
Mycobacterium tuberculosis is responsible for 9 million cases of active tuberculosis and 1.5 million deaths annually. The Baughn lab has been focused on understanding the metabolic basis for susceptibility, resistance and tolerance of M. tuberculosis to various antimicrobial agents. Mainly, they have been applying genetics and biochemical approaches to understand the modes of actions and resistances of the two important anti-tubercular drugs, pyrazinamide (PZA) and paraaminosalicylic acid (PAS). While both of these drugs have been in clinical use for treatment of tuberculosis for over 60 years, we are just now beginning to understand their modes of action. In the case of PZA, these researchers have recently described pantothenate-based antagonism of this and related antimycobacterial agents. Stemming from this work, recent findings indicate that PZA likely acts by disrupting a critical step in fatty acid metabolism. In the case of PAS, the researchers were involved in demonstrating that this drug must be activated within the folate biosynthetic pathway, and that disruption of this bioactivation represents an important mechanism of clinical resistance. Using this new understanding of PAS action, they have identified a novel approach for potentiating action of PAS and related anti-folate drugs by up to 20,000-fold and restoring susceptibility to resistant strains.
In addition to these ongoing projects, the group recently began a new project that utilizes a genomics approach to rapidly and comprehensively probe for novel genetic interactions associated with M. tuberculosis drug susceptibility, resistance, and tolerance. This projects will involve large datasets generated by next-generation sequencing.
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