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Drugging the Folate Pathway in Mycobacterium Tuberculosis: The Role of Multi-Targeting Agents

25 Pages Posted: 10 Sep 2018 Publication Status: Published

See all articles by Behnoush Hajian

Behnoush Hajian

University of Connecticut - Department of Pharmaceutical Sciences

Eric Scocchera

University of Connecticut - Department of Pharmaceutical Sciences

Carolyn Shoen

Syracuse VA Medical Center

Kishore Viswanathan

University of Connecticut - Department of Pharmaceutical Sciences

Narendran G-Dayanandan

University of Connecticut - Department of Pharmaceutical Sciences

Heidi Erlandsen

University of Connecticut - Center for Open Research Resources and Equipment

Alexavier Estrada

University of Connecticut - Department of Pharmaceutical Sciences

Jolanta Krucinska

University of Connecticut - Department of Pharmaceutical Sciences

Katarína Mikušová

Comenius University - Department of Biochemistry

Jana Korduláková

Comenius University - Department of Biochemistry

Michael Cynamon

Syracuse VA Medical Center

Dennis Wright

University of Connecticut - Department of Pharmaceutical Sciences

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Abstract

The folate biosynthetic pathway, responsible for the generation of reduced folate cofactors, offers many druggable targets that have not been exploited in TB therapy. Here, we have identified a series of novel small molecules that interrupt Mycobacterium tuberculosis 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 to that of para-aminosalicylic acid (PAS). We found the bioactive metabolite of PAS, in addition to previously reported activity against DHFR, inhibits flavin-dependent thymidylate synthase (FDTS) 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 a promising strategy to develop novel anti-TB agents.

Suggested Citation

Hajian, Behnoush and Scocchera, Eric and Shoen, Carolyn and Viswanathan, Kishore and G-Dayanandan, Narendran and Erlandsen, Heidi and Estrada, Alexavier and Krucinska, Jolanta and Mikušová, Katarína and Korduláková, Jana and Cynamon, Michael and Wright, Dennis, Drugging the Folate Pathway in Mycobacterium Tuberculosis: The Role of Multi-Targeting Agents (September 6, 2018). Available at SSRN: https://ssrn.com/abstract=3245218 or http://dx.doi.org/10.2139/ssrn.3245218
This version of the paper has not been formally peer reviewed.

Behnoush Hajian

University of Connecticut - Department of Pharmaceutical Sciences

Storrs, CT 06269-1063
United States

Eric Scocchera

University of Connecticut - Department of Pharmaceutical Sciences

Storrs, CT 06269-1063
United States

Carolyn Shoen

Syracuse VA Medical Center

Syracuse, NY 13210
United States

Kishore Viswanathan

University of Connecticut - Department of Pharmaceutical Sciences

Storrs, CT 06269-1063
United States

Narendran G-Dayanandan

University of Connecticut - Department of Pharmaceutical Sciences

Storrs, CT 06269-1063
United States

Heidi Erlandsen

University of Connecticut - Center for Open Research Resources and Equipment

Storrs, CT 06269-1063
United States

Alexavier Estrada

University of Connecticut - Department of Pharmaceutical Sciences

Storrs, CT 06269-1063
United States

Jolanta Krucinska

University of Connecticut - Department of Pharmaceutical Sciences

Storrs, CT 06269-1063
United States

Katarína Mikušová

Comenius University - Department of Biochemistry

SK-84215 Bratislava
Slovakia

Jana Korduláková

Comenius University - Department of Biochemistry

SK-84215 Bratislava
Slovakia

Michael Cynamon

Syracuse VA Medical Center

Syracuse, NY 13210
United States

Dennis Wright (Contact Author)

University of Connecticut - Department of Pharmaceutical Sciences ( email )

Storrs, CT 06269-1063
United States

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