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The Effects of One-Point Mutation on the New Delhi Metallo Beta-Lactamase-1 Resistance toward Carbapenem Antibiotics and β-Lactamase Inhibitors: An In Silico Systematic Approach

Antibiotic resistance has been becoming more and more critical due to bacteria’s evolving hydrolysis enzymes. The NDM-1 enzyme could hydrolyze not only carbapenems but also most of β-lactam’s antibiotics and inhibitors. In fact, variant strains could impose a high impact on the resistance of bacteri...

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Autores principales: Tran, Van-Thanh, Tran, Viet-Hung, Nguyen, Dac-Nhan, Do, Tran-Giang-Son, Vo, Thanh-Phuong, Nguyen, Thi-Thao-Nhung, Huynh, Phuong Nguyen Hoai, Thai, Khac-Minh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9785264/
https://www.ncbi.nlm.nih.gov/pubmed/36555726
http://dx.doi.org/10.3390/ijms232416083
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author Tran, Van-Thanh
Tran, Viet-Hung
Nguyen, Dac-Nhan
Do, Tran-Giang-Son
Vo, Thanh-Phuong
Nguyen, Thi-Thao-Nhung
Huynh, Phuong Nguyen Hoai
Thai, Khac-Minh
author_facet Tran, Van-Thanh
Tran, Viet-Hung
Nguyen, Dac-Nhan
Do, Tran-Giang-Son
Vo, Thanh-Phuong
Nguyen, Thi-Thao-Nhung
Huynh, Phuong Nguyen Hoai
Thai, Khac-Minh
author_sort Tran, Van-Thanh
collection PubMed
description Antibiotic resistance has been becoming more and more critical due to bacteria’s evolving hydrolysis enzymes. The NDM-1 enzyme could hydrolyze not only carbapenems but also most of β-lactam’s antibiotics and inhibitors. In fact, variant strains could impose a high impact on the resistance of bacteria producing NDM-1. Although previous studies showed the effect of some variants toward antibiotics and inhibitors binding, there has been no research systematically evaluating the effects of alternative one-point mutations on the hydrolysis capacity of NDM-1. This study aims to identify which mutants could increase or decrease the effectiveness of antibiotics and β-lactamase inhibitors toward bacteria. Firstly, 35 different variants with a high probability of emergence based on the PAM-1 matrix were constructed and then docked with 5 ligands, namely d-captopril, l-captopril, thiorphan, imipenem, and meropenem. The selected complexes underwent molecular dynamics simulation and free energy binding estimation, with the results showing that the substitutions at residues 122 and 124 most influenced the binding ability of NDM-1 toward inhibitors and antibiotics. The H122R mutant decreases the binding ability between d-captopril and NDM-1 and diminishes the effectiveness of this antibiotic toward Enterobacteriaceae. However, the H122R mutant has a contrary impact on thiorphan, which should be tested in vitro and in vivo in further experiments.
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spelling pubmed-97852642022-12-24 The Effects of One-Point Mutation on the New Delhi Metallo Beta-Lactamase-1 Resistance toward Carbapenem Antibiotics and β-Lactamase Inhibitors: An In Silico Systematic Approach Tran, Van-Thanh Tran, Viet-Hung Nguyen, Dac-Nhan Do, Tran-Giang-Son Vo, Thanh-Phuong Nguyen, Thi-Thao-Nhung Huynh, Phuong Nguyen Hoai Thai, Khac-Minh Int J Mol Sci Article Antibiotic resistance has been becoming more and more critical due to bacteria’s evolving hydrolysis enzymes. The NDM-1 enzyme could hydrolyze not only carbapenems but also most of β-lactam’s antibiotics and inhibitors. In fact, variant strains could impose a high impact on the resistance of bacteria producing NDM-1. Although previous studies showed the effect of some variants toward antibiotics and inhibitors binding, there has been no research systematically evaluating the effects of alternative one-point mutations on the hydrolysis capacity of NDM-1. This study aims to identify which mutants could increase or decrease the effectiveness of antibiotics and β-lactamase inhibitors toward bacteria. Firstly, 35 different variants with a high probability of emergence based on the PAM-1 matrix were constructed and then docked with 5 ligands, namely d-captopril, l-captopril, thiorphan, imipenem, and meropenem. The selected complexes underwent molecular dynamics simulation and free energy binding estimation, with the results showing that the substitutions at residues 122 and 124 most influenced the binding ability of NDM-1 toward inhibitors and antibiotics. The H122R mutant decreases the binding ability between d-captopril and NDM-1 and diminishes the effectiveness of this antibiotic toward Enterobacteriaceae. However, the H122R mutant has a contrary impact on thiorphan, which should be tested in vitro and in vivo in further experiments. MDPI 2022-12-16 /pmc/articles/PMC9785264/ /pubmed/36555726 http://dx.doi.org/10.3390/ijms232416083 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Tran, Van-Thanh
Tran, Viet-Hung
Nguyen, Dac-Nhan
Do, Tran-Giang-Son
Vo, Thanh-Phuong
Nguyen, Thi-Thao-Nhung
Huynh, Phuong Nguyen Hoai
Thai, Khac-Minh
The Effects of One-Point Mutation on the New Delhi Metallo Beta-Lactamase-1 Resistance toward Carbapenem Antibiotics and β-Lactamase Inhibitors: An In Silico Systematic Approach
title The Effects of One-Point Mutation on the New Delhi Metallo Beta-Lactamase-1 Resistance toward Carbapenem Antibiotics and β-Lactamase Inhibitors: An In Silico Systematic Approach
title_full The Effects of One-Point Mutation on the New Delhi Metallo Beta-Lactamase-1 Resistance toward Carbapenem Antibiotics and β-Lactamase Inhibitors: An In Silico Systematic Approach
title_fullStr The Effects of One-Point Mutation on the New Delhi Metallo Beta-Lactamase-1 Resistance toward Carbapenem Antibiotics and β-Lactamase Inhibitors: An In Silico Systematic Approach
title_full_unstemmed The Effects of One-Point Mutation on the New Delhi Metallo Beta-Lactamase-1 Resistance toward Carbapenem Antibiotics and β-Lactamase Inhibitors: An In Silico Systematic Approach
title_short The Effects of One-Point Mutation on the New Delhi Metallo Beta-Lactamase-1 Resistance toward Carbapenem Antibiotics and β-Lactamase Inhibitors: An In Silico Systematic Approach
title_sort effects of one-point mutation on the new delhi metallo beta-lactamase-1 resistance toward carbapenem antibiotics and β-lactamase inhibitors: an in silico systematic approach
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9785264/
https://www.ncbi.nlm.nih.gov/pubmed/36555726
http://dx.doi.org/10.3390/ijms232416083
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