Screening and Identification of a Novel Anti-tuberculosis Compound That Targets Deoxyuridine 5′-Triphosphate Nucleotidohydrolase

Abstract

Tuberculosis (TB) is still a threat to humans worldwide. The rise of drug-resistant TB strains has escalated the need for developing effective anti-TB agents. Deoxyuridine 5′-triphosphate nucleotidohydrolase (dUTPase) is essential for thymidylate biosynthesis to maintain the DNA integrity. In Mycobacterium tuberculosis, dUTPase provides the sole source for thymidylate biosynthesis, which also has the specific five-residue loop and the binding pockets absent in human dUTPase. Therefore, dUTPase has been regarded as a promising anti-TB drug target. Herein, we used a luminescence-based dUTPase assay to search for the inhibitors target M. tuberculosis dUTPase (Mt-dUTPase) and identified compound F0414 as a potent Mt-dUTPase inhibitor with an IC50 of 0.80 ± 0.09 μM. F0414 exhibited anti-TB activity with low cytotoxicity. Molecular docking model and site-directed mutation experiments revealed that P79 was the key residue in the interaction of Mt-dUTPase and F0414. Moreover, F0414 was shown to have stronger binding with Mt-dUTPase than with Mt-P79A-dUTPase by surface plasmon resonance (SPR) detection. Interestingly, F0414 exhibited insensitivity and weak directly binding on human dUTPase compared with that on Mt-dUTPase. All the results highlight that F0414 is the first compound reported to have anti-TB activity by inhibiting Mt-dUTPase, which indicates the potential application in anti-TB therapy.

Comprehensive Coverage on Anti‐mycobacterial Endeavour Reported in 2021

“…SAR studies have not performed by them. [36] Moreover, compound 4 has been found with the IC 50 of 0.80 � 0.09 μM against mycobacterial deoxyuridine triphosphate nucleotidohydrolase (dUTPase), inhibiting the thymidylate biosynthesis in mycobacteria. The molecular docking revealed to inhibit mycobacterial deoxyuridine-5triphosphate nucleotidohydrolase (dUTPase, PDB ID: 1SIX) by binding to its P79 catalytic residue among the five-residue loop, which has been absent within human dUTPase.…”

“…The compound 34 have been found to act on the protein encoded by rpoB gene as revealed through in silico molecular dynamics study and mutation study. [62] Jeyachandran et al have reported 2-(aryloxy methyl)aziridines ( 35) and 2-((3-aryl-1phenylallyloxy)methyl)aziridine (36) with MIC of 0.5 μg/mL having three-fold activity than standard drugs like ciprofloxacin and ethambutol as compared to ethambutol (MIC of 0.5 μg/ mL). [63] Chakravarty et al have reported anthracenyl phosphonate and π-conjugated acid cocrystals (37) with MIC of 1.56 μg/ mL, as active as ethambutol.…”