Mycobacterium tuberculosis dihydrofolate reductase (MtbDHFR)

Mycobacterium tuberculosis dihydrofolate reductase (MtbDHFR) is an essential enzyme required for the survival and proliferation of the causative agent of tuberculosis [1]. It catalyzes the NADPH-dependent reduction of 7,8-dihydrofolate to 5,6,7,8-tetrahydrofolate, a vital cofactor in the biosynthesis of purines, thymidylate, and certain amino acids [2]. By maintaining the pool of tetrahydrofolate, MtbDHFR supports DNA replication and overall bacterial metabolism [3]. Inhibition of this enzyme leads to thymineless death in the bacteria, making it a classic target for antimicrobial therapy [4]. Although several antifolates like trimethoprim are widely used for other bacterial infections, MtbDHFR exhibits intrinsic resistance to many common inhibitors, necessitating the development of more potent and selective agents [5]. Modern drug discovery efforts aim to exploit unique structural features of the MtbDHFR active site, such as the glycerol-binding pocket, to achieve high affinity while minimizing cross-reactivity with the human DHFR ortholog [6]. [1] UniProt (P9WNX1); [2] Zheng, J., et al. Science (2013); [3] PubChem (Target Summary); [4] Wikipedia (Dihydrofolate reductase); [5] Moon, S., et al. Journal of Medicinal Chemistry (2012); [6] Hajian, B., et al. Progress in Medicinal Chemistry (2019).

Other names

DHFRDihydrofolate reductasefolADYR_MYCTU

Competitive inhibition of the enzyme dihydrofolate reductase, which prevents the reduction of 7,8-dihydrofolate to 5,6,7,8-tetrahydrofolate, thereby depleting the pool of tetrahydrofolate cofactors required for the synthesis of thymidylate and purines, leading to the cessation of DNA synthesis and bacterial cell death.