Mutations in catalase-peroxidase KatG from isoniazid resistant Mycobacterium tuberculosis clinical isolates: insights from molecular dynamics simulations

Abstract

The current multidrug therapy for tuberculosis (TB) is based on the use of isoniazid (INH) in combination with other antibiotics such as rifampin, ethambutol and pyrazinamide. Literature reports have shown that Mycobacterium tuberculosis, the causative agent of TB, has become resistant to this treatment by means of point mutations in the target enzymes of these drugs, such as catalase-peroxidase (KatG). By means of equilibrium molecular dynamics in the presence of the ligand, this work evaluated ten point mutations described in the enzyme KatG that are related to resistance to INH . The results showed that the resistance mechanism is related to stereochemical modifications at the N-terminal domain of the protein, which restrict INH access to its catalytic site, not involving mechanisms of electrostatic nature. These results show insights that can be useful for the identification of new anti-TB drugs which may be able to circumvent this mechanism of resistance.

Modeling the structural origins of drug resistance to isoniazid via key mutations in Mycobacterium tuberculosis catalase-peroxidase, KatG

“…The S315T amino acid substitution is therefore thought to be neutral with regards to fitness cost [16]. These results are consistent with the molecular modeling studies of Pimental et al, who studied additional mutations at this position (S315T, S315R, S315I, S315N, S315G) [22].…”

“…In a recent molecular dynamics study, Pimentel and coworkers demonstrated that single amino acid substitutions in Mtb-KatG identified in INH-resistant clinical isolates from Brazil, can decrease the volume of the catalytic cavity as well as potentially alter the positioning of the catalytic heme [22]. The majority of amino acid substitutions studied were either in direct contact with the catalytic heme (S315T, S315R, S315I, S315N, S315G and G273C) or were located in close proximity, within 3 Å (P232R).…”

A bifunctional catalase‐peroxidase, MakatG1, contributes to virulence of Metarhizium acridum by overcoming oxidative stress on the host insect cuticle

“…Since then, KatG homologs, although not ubiquitous, have been found widely distributed in bacteria, as well as in archaea and lower eukaryotes, but not in animals or plants (Z amock y et al, 2008). These enzymes have been of particular interest within the context of microbial pathogens, especially M. tuberculosis where mutations in KatG have been implicated as resulting in resistance to the 'front-line' anti-tubercular drug such as isoniazid (Unissa et al, 2016;Pimentel et al, 2017). KatG has also been implicated in mediating interactions between plant pathogenic microbes and their hosts, where the enzyme has been shown to help the invading microbe mitigate oxidative stress defenses, that is, detoxify production of plant generated ROS (Prapagdee et al, 2004;Jittawuttipoka et al, 2009).…”