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Towards combating antibiotic resistance by exploring the quantitative structure-activity relationship of NDM-1 inhibitors
The emergence of New Delhi metallo-beta-lactamase-1 (NDM-1) has conferred enteric bacteria resistance to almost all beta-lactam antibiotics. Its capability of horizontal transfer through plasmids, amongst humans, animal reservoirs and the environment, has added up to the totality of antimicrobial re...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Leibniz Research Centre for Working Environment and Human Factors
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9755517/ https://www.ncbi.nlm.nih.gov/pubmed/36540675 http://dx.doi.org/10.17179/excli2022-5380 |
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author | Yu, Tianshi Ahmad Malik, Aijaz Anuwongcharoen, Nuttapat Eiamphungporn, Warawan Nantasenamat, Chanin Piacham, Theeraphon |
author_facet | Yu, Tianshi Ahmad Malik, Aijaz Anuwongcharoen, Nuttapat Eiamphungporn, Warawan Nantasenamat, Chanin Piacham, Theeraphon |
author_sort | Yu, Tianshi |
collection | PubMed |
description | The emergence of New Delhi metallo-beta-lactamase-1 (NDM-1) has conferred enteric bacteria resistance to almost all beta-lactam antibiotics. Its capability of horizontal transfer through plasmids, amongst humans, animal reservoirs and the environment, has added up to the totality of antimicrobial resistance control, animal husbandry and food safety. Thus far, there have been no effective drugs for neutralizing NDM-1. This study explores the structure-activity relationship of NDM-1 inhibitors. IC(50) values of NDM-1 inhibitors were compiled from both the ChEMBL database and literature. After curation, a final set of 686 inhibitors were used for machine learning model building using the random forest algorithm against 12 sets of molecular fingerprints. Benchmark results indicated that the KlekotaRothCount fingerprint provided the best overall performance with an accuracy of 0.978 and 0.778 for the training and testing set, respectively. Model interpretation revealed that nitrogen-containing features (KRFPC 4080, KRFPC 3882, KRFPC 677, KRFPC 3608, KRFPC 3750, KRFPC 4287 and KRFPC 3943), sulfur-containing substructures (KRFPC 2855 and KRFPC 4843), aromatic features (KRFPC 1566, KRFPC 1564, KRFPC 1642, KRFPC 3608, KRFPC 4287 and KRFPC 3943), carbonyl features (KRFPC 1193 and KRFPC 3025), aliphatic features (KRFPC 2975, KRFPC 297, KRFPC 3224 and KRFPC 669) are features contributing to NDM-1 inhibitory activity. It is anticipated that findings from this study would help facilitate the drug discovery of NDM-1 inhibitors by providing guidelines for further lead optimization. |
format | Online Article Text |
id | pubmed-9755517 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Leibniz Research Centre for Working Environment and Human Factors |
record_format | MEDLINE/PubMed |
spelling | pubmed-97555172022-12-19 Towards combating antibiotic resistance by exploring the quantitative structure-activity relationship of NDM-1 inhibitors Yu, Tianshi Ahmad Malik, Aijaz Anuwongcharoen, Nuttapat Eiamphungporn, Warawan Nantasenamat, Chanin Piacham, Theeraphon EXCLI J Original Article The emergence of New Delhi metallo-beta-lactamase-1 (NDM-1) has conferred enteric bacteria resistance to almost all beta-lactam antibiotics. Its capability of horizontal transfer through plasmids, amongst humans, animal reservoirs and the environment, has added up to the totality of antimicrobial resistance control, animal husbandry and food safety. Thus far, there have been no effective drugs for neutralizing NDM-1. This study explores the structure-activity relationship of NDM-1 inhibitors. IC(50) values of NDM-1 inhibitors were compiled from both the ChEMBL database and literature. After curation, a final set of 686 inhibitors were used for machine learning model building using the random forest algorithm against 12 sets of molecular fingerprints. Benchmark results indicated that the KlekotaRothCount fingerprint provided the best overall performance with an accuracy of 0.978 and 0.778 for the training and testing set, respectively. Model interpretation revealed that nitrogen-containing features (KRFPC 4080, KRFPC 3882, KRFPC 677, KRFPC 3608, KRFPC 3750, KRFPC 4287 and KRFPC 3943), sulfur-containing substructures (KRFPC 2855 and KRFPC 4843), aromatic features (KRFPC 1566, KRFPC 1564, KRFPC 1642, KRFPC 3608, KRFPC 4287 and KRFPC 3943), carbonyl features (KRFPC 1193 and KRFPC 3025), aliphatic features (KRFPC 2975, KRFPC 297, KRFPC 3224 and KRFPC 669) are features contributing to NDM-1 inhibitory activity. It is anticipated that findings from this study would help facilitate the drug discovery of NDM-1 inhibitors by providing guidelines for further lead optimization. Leibniz Research Centre for Working Environment and Human Factors 2022-11-16 /pmc/articles/PMC9755517/ /pubmed/36540675 http://dx.doi.org/10.17179/excli2022-5380 Text en Copyright © 2022 Yu et al. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ) You are free to copy, distribute and transmit the work, provided the original author and source are credited. |
spellingShingle | Original Article Yu, Tianshi Ahmad Malik, Aijaz Anuwongcharoen, Nuttapat Eiamphungporn, Warawan Nantasenamat, Chanin Piacham, Theeraphon Towards combating antibiotic resistance by exploring the quantitative structure-activity relationship of NDM-1 inhibitors |
title | Towards combating antibiotic resistance by exploring the quantitative structure-activity relationship of NDM-1 inhibitors |
title_full | Towards combating antibiotic resistance by exploring the quantitative structure-activity relationship of NDM-1 inhibitors |
title_fullStr | Towards combating antibiotic resistance by exploring the quantitative structure-activity relationship of NDM-1 inhibitors |
title_full_unstemmed | Towards combating antibiotic resistance by exploring the quantitative structure-activity relationship of NDM-1 inhibitors |
title_short | Towards combating antibiotic resistance by exploring the quantitative structure-activity relationship of NDM-1 inhibitors |
title_sort | towards combating antibiotic resistance by exploring the quantitative structure-activity relationship of ndm-1 inhibitors |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9755517/ https://www.ncbi.nlm.nih.gov/pubmed/36540675 http://dx.doi.org/10.17179/excli2022-5380 |
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