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.

Highlights

  • Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis (M. tuberculosis), which is the top cause of death from infectious disease [World Health organization, 2020a]

  • We focused on screening inhibitors of M. tuberculosis Deoxyuridine triphosphate nucleotidohydrolase (dUTPase) (Mt-dUTPase)

  • Mt-dUTPase can hydrolyze dUTP to dUMP in M. tuberculosis

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Summary

Introduction

Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis (M. tuberculosis), which is the top cause of death from infectious disease [World Health organization, 2020a]. It has been a huge threat to public health worldwide for a long time, with about 10 million people infected each year [World Health organization, 2020b]. After a long time of inactivity, increasing numbers of new antiTB drugs have been seen in recent years (Singh et al, 2020). Both bedaquiline and delamanid are new anti-TB drugs approved in almost half a century (Pym et al, 2016; Liu et al, 2018; Li et al, 2019). With the increasing use in clinic, the resistance toward bedaquiline and delamanid appeared (Liu et al, 2018; Degiacomi et al, 2020). Novel drug targets for developing new anti-TB drugs are still necessary

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