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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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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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. |
format | Online Article Text |
id | pubmed-9785264 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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