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Screening of MMV pandemic response and pathogen box compounds against pan-drug-resistant Klebsiella pneumoniae to identify potent inhibitory compounds

BACKGROUND: The recent emergence of pan-drug-resistant (PDR) K. pneumoniae strains hinders the success rate of treatment procedures for patients. High mortality, extended duration of hospitalization with high costs is associated with such infections. Discovery and identification of new drugs are ine...

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Autores principales: Sivasankar, Seshan, Premnath, Mari Abinaya, Boppe, Appalaraju, Grobusch, Martin Peter, Jeyaraj, Sankarganesh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10690571/
https://www.ncbi.nlm.nih.gov/pubmed/38046897
http://dx.doi.org/10.1016/j.nmni.2023.101193
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author Sivasankar, Seshan
Premnath, Mari Abinaya
Boppe, Appalaraju
Grobusch, Martin Peter
Jeyaraj, Sankarganesh
author_facet Sivasankar, Seshan
Premnath, Mari Abinaya
Boppe, Appalaraju
Grobusch, Martin Peter
Jeyaraj, Sankarganesh
author_sort Sivasankar, Seshan
collection PubMed
description BACKGROUND: The recent emergence of pan-drug-resistant (PDR) K. pneumoniae strains hinders the success rate of treatment procedures for patients. High mortality, extended duration of hospitalization with high costs is associated with such infections. Discovery and identification of new drugs are inevitable to combat PDR clinical pathogens. We aim to identify and evaluate new compounds in vitro against a PDR clinical K. pneumoniae isolate using compounds of Pathogen Box and Pandemic Response Box from Medicines for Malaria Venture (MMV). METHODS: The PDR strain was initially screened with the 601 compounds from both Boxes at 10 ​μM concentration. Formation of dormant cells against the drug activity was assessed using persister assay. MIC was determined for the drugs inhibiting PDR K. pneumoniae during initial screening. RESULTS: Five compounds were identified to inhibit the test strain. MMV1580854 (94.60 ​%), MMV1579788 (94.65 ​%), MMV1578574 (eravacycline; 93.13 ​%), MMV1578566 (epetraborole; 95.29 ​%) and MMV1578564 (96.32 ​%) were able to exhibit a higher percentage of growth inhibition. Persisters were found to be growing in a range from 10(4) to 10(7) ​CFU/ml. Minimum inhibitory concentrations (MIC) of all compounds were ≥ 2 ​μM except for MMV1579788, which had a MIC of ≥ 5 ​μM. CONCLUSION: Five novel compounds were identified against the highly evolved pan-drug-resistant K. pneumoniae. Among the five, epetraborole andMMV1578564 were identified as highly potent based on the persister frequency and MICs. The pan-drug resistant clinical isolate used in this study was found to be acting differently from the reference or wild type strains against the test compounds in a previous study.
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spelling pubmed-106905712023-12-02 Screening of MMV pandemic response and pathogen box compounds against pan-drug-resistant Klebsiella pneumoniae to identify potent inhibitory compounds Sivasankar, Seshan Premnath, Mari Abinaya Boppe, Appalaraju Grobusch, Martin Peter Jeyaraj, Sankarganesh New Microbes New Infect Original Article BACKGROUND: The recent emergence of pan-drug-resistant (PDR) K. pneumoniae strains hinders the success rate of treatment procedures for patients. High mortality, extended duration of hospitalization with high costs is associated with such infections. Discovery and identification of new drugs are inevitable to combat PDR clinical pathogens. We aim to identify and evaluate new compounds in vitro against a PDR clinical K. pneumoniae isolate using compounds of Pathogen Box and Pandemic Response Box from Medicines for Malaria Venture (MMV). METHODS: The PDR strain was initially screened with the 601 compounds from both Boxes at 10 ​μM concentration. Formation of dormant cells against the drug activity was assessed using persister assay. MIC was determined for the drugs inhibiting PDR K. pneumoniae during initial screening. RESULTS: Five compounds were identified to inhibit the test strain. MMV1580854 (94.60 ​%), MMV1579788 (94.65 ​%), MMV1578574 (eravacycline; 93.13 ​%), MMV1578566 (epetraborole; 95.29 ​%) and MMV1578564 (96.32 ​%) were able to exhibit a higher percentage of growth inhibition. Persisters were found to be growing in a range from 10(4) to 10(7) ​CFU/ml. Minimum inhibitory concentrations (MIC) of all compounds were ≥ 2 ​μM except for MMV1579788, which had a MIC of ≥ 5 ​μM. CONCLUSION: Five novel compounds were identified against the highly evolved pan-drug-resistant K. pneumoniae. Among the five, epetraborole andMMV1578564 were identified as highly potent based on the persister frequency and MICs. The pan-drug resistant clinical isolate used in this study was found to be acting differently from the reference or wild type strains against the test compounds in a previous study. Elsevier 2023-11-07 /pmc/articles/PMC10690571/ /pubmed/38046897 http://dx.doi.org/10.1016/j.nmni.2023.101193 Text en © 2023 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Sivasankar, Seshan
Premnath, Mari Abinaya
Boppe, Appalaraju
Grobusch, Martin Peter
Jeyaraj, Sankarganesh
Screening of MMV pandemic response and pathogen box compounds against pan-drug-resistant Klebsiella pneumoniae to identify potent inhibitory compounds
title Screening of MMV pandemic response and pathogen box compounds against pan-drug-resistant Klebsiella pneumoniae to identify potent inhibitory compounds
title_full Screening of MMV pandemic response and pathogen box compounds against pan-drug-resistant Klebsiella pneumoniae to identify potent inhibitory compounds
title_fullStr Screening of MMV pandemic response and pathogen box compounds against pan-drug-resistant Klebsiella pneumoniae to identify potent inhibitory compounds
title_full_unstemmed Screening of MMV pandemic response and pathogen box compounds against pan-drug-resistant Klebsiella pneumoniae to identify potent inhibitory compounds
title_short Screening of MMV pandemic response and pathogen box compounds against pan-drug-resistant Klebsiella pneumoniae to identify potent inhibitory compounds
title_sort screening of mmv pandemic response and pathogen box compounds against pan-drug-resistant klebsiella pneumoniae to identify potent inhibitory compounds
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10690571/
https://www.ncbi.nlm.nih.gov/pubmed/38046897
http://dx.doi.org/10.1016/j.nmni.2023.101193
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