Analysis of interactions of clinical mutants of catalase-peroxidase (KatG) responsible for isoniazid resistance in Mycobacterium tuberculosis with derivatives of isoniazid

Unissa, Ameeruddin Nusrath; C, George Priya Doss; Kumar, Thirumal; Sukumar, Swathi; Lakshmi, Appisetty Ramya; Hanna, Luke Elizabeth

doi:10.1016/j.jgar.2017.06.014

Cited by 8 publications

(4 citation statements)

References 31 publications

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“…Previous in silico studies, for instance, using INH derivatives illustrated that INH’s binding energy in the mutants can be refined through INH redesign, hence improving the INH binding ability in mutants. 39 To this effect, we modeled 3D structures of KatG mutant proteins and investigated their conformational changes over time through molecular dynamics (MD) trajectory analysis. Post-MD analysis revealed a diverse array of effects of the mutations on the KatG protein structure characterized with changes in protein compactness and flexibility of the mutant systems in comparison to the wild-type (WT).…”

Section: Introductionmentioning

confidence: 99%

“…To further uncover drug resistance mechanisms of INH as a poorly understood area, we applied computational approaches that we have recently developed. − Our objective was to discern the structural and functional effects of 11 high confidence (HC) mutations (S140N, S140R, G279D, G285D, S315I, S315N, S315R, S315T, G316D, S457I, and G593D), so as to guide the process of designing next generation antitubercular drugs. Previous in silico studies, for instance, using INH derivatives illustrated that INH’s binding energy in the mutants can be refined through INH redesign, hence improving the INH binding ability in mutants . To this effect, we modeled 3D structures of KatG mutant proteins and investigated their conformational changes over time through molecular dynamics (MD) trajectory analysis.…”

Section: Introductionmentioning

confidence: 99%

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Deciphering Isoniazid Drug Resistance Mechanisms on Dimeric Mycobacterium tuberculosis KatG via Post-molecular Dynamics Analyses Including Combined Dynamic Residue Network Metrics

et al. 2022

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Resistance mutations in Mycobacterium tuberculosis ( Mtb ) catalase peroxidase protein (KatG), an essential enzyme in isoniazid (INH) activation, reduce the sensitivity of Mtb to first-line drugs, hence presenting challenges in tuberculosis (TB) management. Thus, understanding the mutational imposed resistance mechanisms remains of utmost importance in the quest to reduce the TB burden. Herein, effects of 11 high confidence mutations in the KatG structure and residue network communication patterns were determined using extensive computational approaches. Combined traditional post-molecular dynamics analysis and comparative essential dynamics revealed that the mutant proteins have significant loop flexibility around the heme binding pocket and enhanced asymmetric protomer behavior with respect to wild-type (WT) protein. Heme contact analysis between WT and mutant proteins identified a reduction to no contact between heme and residue His270, a covalent bond vital for the heme-enabled KatG catalytic activity. Betweenness centrality calculations showed large hub ensembles with new hubs especially around the binding cavity and expanded to the dimerization domain via interface in the mutant systems, providing possible compensatory allosteric communication paths for the active site as a result of the mutations which may destabilize the heme binding pocket and the loops in its vicinity. Additionally, an interesting observation came from Eigencentrality hubs, most of which are located in the C-terminal domain, indicating relevance of the domain in the protease functionality. Overall, our results provide insight toward the mechanisms involved in KatG-INH resistance in addition to identifying key regions in the enzyme functionality, which can be used for future drug design.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Deciphering Isoniazid Drug Resistance Mechanisms on Dimeric Mycobacterium tuberculosis KatG via Post-molecular Dynamics Analyses Including Combined Dynamic Residue Network Metrics

et al. 2022

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“…Це багатофункціональні гемозалежні ферменти, які беруть активну участь у окисно-відновних процесах антиоксидантного захисту мікробної клітини (Sepasi Tehrani & Moosavi-Movahedi, 2018). У літературних джерелах повідомлено, що каталаза сприяє здатності M. tuberculosis виживати в контамінованих тканинах господаря (Machuqueiro et al, 2017;Unissa, et al 2017), що було підтверджено лабораторними експериментами на мишах і морських свинках (Li et al, 1998). У роботі Manca et al, (1998) досліджували каталазну та пероксидазну активність лабораторних, клінічних і рекомбінантних штамів M. tuberculosis, їх вимірювали як внутрішньоклітинно (в моноцитах людини), так і в живильному середовищі.…”

Section: обговоренняunclassified

Dependending of biochemical activities Mycobacterium bovis on passages and temperature of cultivation

Tkachenko¹,

Kozak²,

Bilan³

et al. 2019

TAVM

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The tuberculosis of cattle remains a serious problem both in Ukraine and for the whole world for many years. In spite of the fact that in science now much known about the agent of tuberculosis, some of the mechanisms through which mycobacteria manage to survive in the conditions of macroorganism and the environment have not been studied. Difficulties in overcoming of tuberculosis and mycobacteriosis can be connected with the incredible plasticity of life processes within the bacterial cells of mycobacteria. Understanding the enzymatic processes in the bacterial cell and their changes in response to the influence of external factors can lead to an understanding of the complex mechanism of adaptation and survival of mycobacteria, both in macroorganism and in the environment. The aim of our research was to determine the influence of the number passage of high-resistance strain Mycobacterium bovis in the organism of guinea pigs (Cavia porcellus), the temperature of cultivation (3°C; 37°C) on changes in biochemical activity. The ability of M. bovis and dissociative forms to grow on a nutrient medium with addition of sodium salicylate and on usual nutrient media (meat-peptone extract and meat-peptone agar) was investigated. The research was carried out using the high-virulence strain M. bovis, which was stored in the museum of the Laboratory of the Department of epizootology and infectious diseases of Dnipro State Agrarian and Economic University during 10-13 years, as well as dissociative forms 117-a, b, v, 118. The results of the research indicate the ability of mycobacteria to change biochemical activity under the influence of external factors. It has been established that the number of passages through a dense egg nutrient medium does not have a direct effect on the enzymatic activity of M. bovis. In dissociative forms with increasing number of inoculation of subcultures, the activity of nitrate reductase increases and peroxidase activity, dehydrogenase activity and catalase activity decrease. It has been found that low positive culturing temperature (3 ºС) contributes to increase of catalase activity and hydrolysis ability of Tween-80. It has been determined that after passage through the organism of guinea pigs, M. bovis increase the activity of dehydrogenase and catalase and reduce nitrate reductase activity and hydrolysis ability of TWIN-80. So, the results presented in the article shows that the existence of mycobacteria is able to change the function of their own systems according to the changes of environment conditions..

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“…However, mutations in katG led inability to activate INH. Mutation of katG at Ser315 is most prevalent and virulent among other several mutations have been identified so far [5,[9][10][11][12]. In our previous studies, we have designed and identified some potential anti-bacterial and anti-tubercular chemical entities as DNA gyrase B (Gyr B) inhibitors using de novo design technique, pharmacophore-based virtual screening, molecular docking and dynamics simulations studies [4,13].…”

Section: Introductionmentioning

confidence: 99%

Pharmacoinformatics-based identification of anti-bacterial catalase-peroxidase enzyme inhibitors

Jangam

Bhowmick

Chorge

et al. 2019

Computational Biology and Chemistry

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Analysis of interactions of clinical mutants of catalase-peroxidase (KatG) responsible for isoniazid resistance in Mycobacterium tuberculosis with derivatives of isoniazid

Cited by 8 publications

References 31 publications

Deciphering Isoniazid Drug Resistance Mechanisms on Dimeric Mycobacterium tuberculosis KatG via Post-molecular Dynamics Analyses Including Combined Dynamic Residue Network Metrics

Deciphering Isoniazid Drug Resistance Mechanisms on Dimeric Mycobacterium tuberculosis KatG via Post-molecular Dynamics Analyses Including Combined Dynamic Residue Network Metrics

Dependending of biochemical activities Mycobacterium bovis on passages and temperature of cultivation

Pharmacoinformatics-based identification of anti-bacterial catalase-peroxidase enzyme inhibitors

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