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Cell Chem Biol. 2019 Mar 8. pii: S2451-9456(19)30068-6. doi: 10.1016/j.chembiol.2019.02.013. [Epub ahead of print]

Drugging the Folate Pathway in Mycobacterium tuberculosis: The Role of Multi-targeting Agents.

Author information

1
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA.
2
Syracuse VA Medical Center, Syracuse, NY 13210, USA.
3
Center for Open Research Resources and Equipment, University of Connecticut, Storrs, CT 06269, USA.
4
Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Mlynská Dolina CH-1, Ilkovičova 6, 842 15, Bratislava, Slovakia.
5
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA. Electronic address: dennis.wright@uconn.edu.

Abstract

The folate biosynthetic pathway offers many druggable targets that have yet to be exploited in tuberculosis therapy. Herein, we have identified a series of small molecules that interrupt Mycobacterium tuberculosis (Mtb) folate metabolism by dual targeting of dihydrofolate reductase (DHFR), a key enzyme in the folate pathway, and its functional analog, Rv2671. We have also compared the antifolate activity of these compounds with that of para-aminosalicylic acid (PAS). We found that the bioactive metabolite of PAS, in addition to previously reported activity against DHFR, inhibits flavin-dependent thymidylate synthase in Mtb, suggesting a multi-targeted mechanism of action for this drug. Finally, we have shown that antifolate treatment in Mtb decreases the production of mycolic acids, most likely due to perturbation of the activated methyl cycle. We conclude that multi-targeting of the folate pathway in Mtb is associated with highly potent anti-mycobacterial activity.

KEYWORDS:

Mycobacterium tuberculosis; Rv2671; antifolates; antimicrobial resistance; dihydrofolate reductase; flavin-dependent thymidylate synthase; multi-targeting; mycolic acids; para-aminosalicylic acid; tuberculosis

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