Modification of drug-binding proteins associated with the efflux pump in MDR-MTB in course of evolution: an unraveled clue based on in silico approach

Panja, Anindya Sundar; Sarkar, Aniket; Biswas, Raju; Bandyopadhyay, Bidyut; Bandopadhyay, Rajib

doi:10.1038/s41429-019-0146-3

Cited by 6 publications

(3 citation statements)

References 18 publications

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“…In silico analysis for research regarding antimicrobial resistance will open a new avenue for scientists and the pharmaceutical industry as well as policymakers [88]. Molecular docking and homology modeling of the available drugs can be easily investigated [69,89]. In silico study will also help in understanding the drug resistant mechanism, prediction of traits responsible for AMR, protein-protein interaction, changes in structural conformation and analysis of mutational hotspot region [90].…”

Section: In Silico Analysismentioning

confidence: 99%

Review on Multiple Facets of Drug Resistance: A Rising Challenge in the 21st Century

Saha

Sarkar

2021

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With the advancements of science, antibiotics have emerged as an amazing gift to the human and animal healthcare sectors for the treatment of bacterial infections and other diseases. However, the evolution of new bacterial strains, along with excessive use and reckless consumption of antibiotics have led to the unfolding of antibiotic resistances to an excessive level. Multidrug resistance is a potential threat worldwide, and is escalating at an extremely high rate. Information related to drug resistance, and its regulation and control are still very little. To interpret the onset of antibiotic resistances, investigation on molecular analysis of resistance genes, their distribution and mechanisms are urgently required. Fine-tuned research and resistance profile regarding ESKAPE pathogen is also necessary along with other multidrug resistant bacteria. In the present scenario, the interaction of bacterial infections with SARS-CoV-2 is also crucial. Tracking and in-silico analysis of various resistance mechanisms or gene/s are crucial for overcoming the problem, and thus, the maintenance of relevant databases and wise use of antibiotics should be promoted. Creating awareness of this critical situation among individuals at every level is important to strengthen the fight against this fast-growing calamity. The review aimed to provide detailed information on antibiotic resistance, its regulatory molecular mechanisms responsible for the resistance, and other relevant information. In this article, we tried to focus on the correlation between antimicrobial resistance and the COVID-19 pandemic. This study will help in developing new interventions, potential approaches, and strategies to handle the complexity of antibiotic resistance and prevent the incidences of life-threatening infections.

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Section: In Silico Analysismentioning

confidence: 99%

Review on Multiple Facets of Drug Resistance: A Rising Challenge in the 21st Century

Saha

Sarkar

2021

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“…Additionally, a recent study advises that Rv1634 protein is one of the 10 proteins crucial in the survival and in vivo growth of Mtb 19 . Furthermore, an in silico study state that in due course of time, Mtb MDR strains had evolved drug resistance by altering two of its transporter protein pumps, Rv1634 protein and Rv1258c protein, to extrude active drug compounds from their cellular environment 20 . A common characteristic of MDR proteins is the ability to transport various substrates, so there are fair chances that it may play as a potential target for new drugs in the future.…”

Section: Introductionmentioning

confidence: 99%

“…19 Furthermore, an in silico study state that in due course of time, Mtb MDR strains had evolved drug resistance by altering two of its transporter protein pumps, Rv1634 protein and Rv1258c protein, to extrude active drug compounds from their cellular environment. 20 A common characteristic of MDR proteins is the ability to transport various substrates, so there are fair chances that it may play as a potential target for new drugs in the future. Hence, the current study may enhance the understanding of mechanistic basis of drug binding, substrate specificity, and the transport of the MFS efflux pumps at molecular levels in general and specifically for multidrug-resistant Mtb strains.…”

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confidence: 99%

Molecular insights into the differential efflux mechanism of Rv1634 protein, a multidrug transporter of major facilitator superfamily in Mycobacterium tuberculosis

Singh

Akhter

2021

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Currently, multidrug‐resistant tuberculosis (MDR‐TB) is a public health crisis and a major health security threat globally. In Mycobacterium tuberculosis (Mtb), major facilitator superfamily (MFS) is the largest group of secondary active transporters. Along with the transport of their natural substrates, MFS proteins were involved in a drug efflux mechanism that ultimately lead to resistance against available anti‐TB drugs in Mtb. In the present study, the three‐dimensional structure model of an MFS protein, Rv1634, a probable multidrug transporter from Mtb, was generated using homology modeling. The protein structure model was found in inward‐open conformation having 14 transmembrane helices. In addition, a central transport channel was deduced across the protein, and a single binding pocket was identified halfway through the central cavity by structural alignment with the homologous protein structures. Further, Rv1634 protein was studied based on the differential structural behavior of apo and ligand‐bound forms. All the protein systems were inserted into a phospholipid bilayer to characterize the conformational dynamics of the protein using molecular dynamics (MD) simulations. Detailed analysis of the MD trajectories showed the diverse substrate specificity of the binding pocket for the antibiotics that caused differential movement in the ciprofloxacin and norfloxacin, to which Mtb strains have now become resistant. The expulsion of the drugs outside the bacterial cell occurs through the alternating‐access mechanism of N and C‐terminal domains, which is intriguing and essential to the understanding the drug resistance mechanism in pathogenic bacteria.

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Alterations in molecular response of Mycobacterium tuberculosis against anti-tuberculosis drugs

et al. 2022

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Modification of drug-binding proteins associated with the efflux pump in MDR-MTB in course of evolution: an unraveled clue based on in silico approach

Cited by 6 publications

References 18 publications

Review on Multiple Facets of Drug Resistance: A Rising Challenge in the 21st Century

Review on Multiple Facets of Drug Resistance: A Rising Challenge in the 21st Century

Molecular insights into the differential efflux mechanism of Rv1634 protein, a multidrug transporter of major facilitator superfamily in Mycobacterium tuberculosis

Alterations in molecular response of Mycobacterium tuberculosis against anti-tuberculosis drugs

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