Structural analysis of the interaction of embB protein mutations of Mycobacterium tuberculosis with ethambutol and their effect on the interaction

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a global health challenge exacerbated by the emergence of drug-resistant strains. Ethambutol is a critical first-line anti-TB drug targeting the embB protein, an enzyme essential for mycobacterial cell wall biosynthesis. Mutations in the embB gene are associated with resistance to ethambutol, reducing treatment efficacy and complicating disease management. This study aimed at investigating the interaction between the wild-type and specific mutant embB proteins and ethambutol and to investigate the effects of these specific embB mutations on this interaction. Computational docking and structural interaction analysis of the wild-type embB protein with Protein Data Bank (PDB) ID: 7BVF and its common mutants (M306V, M306L, E378A) with ethambutol was performed using PyRx software and LigPlot respectively. Binding affinities were calculated and the interaction sites were identified and analysed using molecular docking techniques and 2D ligand interaction diagrams respectively. The wild-type embB protein demonstrated a binding affinity of -4.8 kcal/mol with ethambutol, involving key residues such as Leu561, Thr564, Tyr502 and Asp498, forming a network of hydrogen bonds ranging from 2.87 Å to 3.26 Å. In contrast, embB mutants exhibited reduced binding affinities: -3.8 kcal/mol for M306V, -3.9 kcal/mol for M306L, and -4.7 kcal/mol for E378A. These mutations disrupted the hydrogen bond network, involving fewer residues and exhibiting weaker interactions with ethambutol. The findings highlight the critical role of specific residues in the embB protein for maintaining high-affinity interactions with ethambutol. Mutations in these residues significantly reduce drug binding, contributing to resistance. This study underscores the importance of targeting these mutations for the development of novel therapeutic agents and suggests the need for enhanced diagnostic tools to detect embB mutations in clinical isolates for effective TB management.