Identification and Repurposing of Trisubstituted Harmine Derivatives as Novel Inhibitors of Mycobacterium tuberculosis Phosphoserine Phosphatase.

Elise Pierson,Marie Haufroid,Ramandeep Singh,Pankaj Chopra,Tannu Priya Gosain,Johan Wouters

doi:10.3390/molecules25020415

Abstract

Mycobacterium tuberculosis is still the deadliest bacterial pathogen worldwide and the increasing number of multidrug-resistant tuberculosis cases further complicates this global health issue. M. tuberculosis phosphoserine phosphatase SerB2 is a promising target for drug design. Besides being a key essential metabolic enzyme of the pathogen’s serine pathway, it appears to be involved in immune evasion mechanisms. In this work, a malachite green-based phosphatase assay has been used to screen 122 compounds from an internal chemolibrary. Trisubstituted harmine derivatives were found among the best hits that inhibited SerB2 activity. Synthesis of an original compound helped to discuss a brief structure activity relationship evaluation. Kinetics experiments showed that the most potent derivatives inhibit the phosphatase in a parabolic competitive fashion with apparent inhibition constants () values in the micromolar range. Their interaction modes with the enzyme were investigated through induced fit docking experiments, leading to results consistent with the experimental data. Cellular assays showed that the selected compounds also inhibited M. tuberculosis growth in vitro. Those promising results may provide a basis for the development of new antimycobacterial agents targeting SerB2.

Highlights

Tuberculosis (TB), a disease caused by Mycobacterium tuberculosis (Mtb), is still a matter of concern for the World Health Organization (WHO)
Subsequent enzymatic assays were performed in the presence of 122 different therapeutically intended compounds made available by the NAMEDIC research center to identify new anti-TB agents targeting SerB2 (Figure 1A)
A first screening of 122 compounds from our internal chemolibrary led to the identification of a series of harmine derivatives targeting SerB2, an essential metabolic enzyme and suspected virulence factor of M. tuberculosis

Summary

Introduction

Tuberculosis (TB), a disease caused by Mycobacterium tuberculosis (Mtb), is still a matter of concern for the World Health Organization (WHO). An estimated 10 million people fall ill with TB. This number has been stable in recent years and the number of casualties is slowly decreasing, drug-resistant cases are on the rise [1,2,3]. To achieve its final goal, a TB-free world by 2035, the WHO invites researchers to find new diagnostics tools, drug-targets, scaffolds and vaccines [4]. To this end, many enzymes from Mtb metabolic pathways, such as secretory tyrosine phosphatases (MptpA, MptpB) or the inosine 50 -monophosphate dehydrogenase (GuaB2), have been identified and characterized [5,6,7,8]. Many amino acid biosynthetic pathways, including those of arginine and Molecules 2020, 25, 415; doi:10.3390/molecules25020415 www.mdpi.com/journal/molecules

Objectives

Methods

Results

Conclusion