Abstract
para-Aminosalicylic acid (PAS) is a second-line anti-tubercular drug that is used for the treatment of drug-resistant tuberculosis (TB). PAS efficacy in the treatment of TB is limited by its lower potency against Mycobacterium tuberculosis relative to many other drugs in the TB treatment arsenal. It is known that intrinsic metabolites, such as, para-aminobenzoic acid (PABA) and methionine, antagonize PAS and structurally related anti-folate drugs. While the basis for PABA-mediated antagonism of anti-folates is understood, the mechanism for methionine-based antagonism remains undefined. In the present study, we used both targeted and untargeted approaches to identify factors associated with methionine-mediated antagonism of PAS activity. We found that synthesis of folate precursors as well as a putative amino acid transporter, designated MetM, play crucial roles in this process. Disruption of metM by transposon insertion resulted in a ≥30-fold decrease in uptake of methionine in M. bovis BCG, indicating that metM is the major facilitator of methionine transport. We also discovered that intracellular biotin confers intrinsic PAS resistance in a methionine-independent manner. Collectively, our results demonstrate that methionine-mediated antagonism of anti-folate drugs occurs through sustained production of folate precursors.
Highlights
Mycobacterium tuberculosis is responsible for ∼10.4 million new cases of active tuberculosis (TB) and 1.3 million deaths annually (World Health Organization, 2017)
Since para-Aminosalicylic acid (PAS), sulfamethoxazole, and rifampicin susceptibilities of the bioB::himar1 were dependent upon the concentration of supplemented biotin, these results indicated that defect in biotin cofactor biosynthesis in the bioB::himar1 strain is responsible for increased susceptibility to PAS, sulfamethoxazole and rifampicin
Anti-folate drugs antagonized by methionine are antagonized by para-aminobenzoic acid (PABA), a folate precursor
Summary
Mycobacterium tuberculosis is responsible for ∼10.4 million new cases of active tuberculosis (TB) and 1.3 million deaths annually (World Health Organization, 2017). While TB chemotherapeutic intervention is highly successful in curing drug-susceptible TB infections, therapy is challenging, in part, because it requires a minimum of 6 months of treatment with drugs associated with adverse reactions. Emergence of M. tuberculosis strains with resistance to first-line anti-tubercular agents led to the resurgence of PAS as an second-line drug to treat infections that failed to respond to standard short-course therapy (Donald and Diacon, 2015). Compared to many other anti-tubercular drugs, PAS is less potent and is associated with a high rate of gastrointestinal distress which limits its use to the treatment of multi-drug resistant TB for which there are few other treatment options (Zumla et al, 2013). It is important to develop novel strategies to enhance PAS potency, limit adverse reactions and improve treatment success rates
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
