TY - JOUR
T1 - Screening of MMV pandemic response and pathogen box compounds against pan-drug-resistant Klebsiella pneumoniae to identify potent inhibitory compounds
AU - Sivasankar, Seshan
AU - Premnath, Mari Abinaya
AU - Boppe, Appalaraju
AU - Grobusch, Martin Peter
AU - Jeyaraj, Sankarganesh
N1 - Funding Information: We are sincerely grateful to PSG Institutions Management for Laboratory facilities and infrastructure. We thank Medicines for Malaria Venture (MMV, Switzerland) for support and supply of the Pathogen Box and Pandemic Response Box. Publisher Copyright: © 2023 The Authors
PY - 2023/10
Y1 - 2023/10
N2 - 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 104 to 107 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.
AB - 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 104 to 107 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.
KW - Antimicrobial activity
KW - Klebsiella pneumonia
KW - Pathogen and pandemic response box
KW - Persister assay
UR - http://www.scopus.com/inward/record.url?scp=85178261103&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.nmni.2023.101193
DO - https://doi.org/10.1016/j.nmni.2023.101193
M3 - Article
C2 - 38046897
SN - 2052-2975
VL - 55
SP - 101193
JO - New Microbes and New Infections
JF - New Microbes and New Infections
M1 - 101193
ER -