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J Chem Inf Model ; 64(10): 3977-3991, 2024 May 27.
Artículo en Inglés | MEDLINE | ID: mdl-38727192

RESUMEN

The worldwide spread of the metallo-ß-lactamases (MBL), especially New Delhi metallo-ß-lactamase-1 (NDM-1), is threatening the efficacy of ß-lactams, which are the most potent and prescribed class of antibiotics in the clinic. Currently, FDA-approved MBL inhibitors are lacking in the clinic even though many strategies have been used in inhibitor development, including quantitative high-throughput screening (qHTS), fragment-based drug discovery (FBDD), and molecular docking. Herein, a machine learning-based prediction tool is described, which was generated using results from HTS of a large chemical library and previously published inhibition data. The prediction tool was then used for virtual screening of the NIH Genesis library, which was subsequently screened using qHTS. A novel MBL inhibitor was identified and shown to lower minimum inhibitory concentrations (MICs) of Meropenem for a panel of E. coli and K. pneumoniae clinical isolates expressing NDM-1. The mechanism of inhibition of this novel scaffold was probed utilizing equilibrium dialyses with metal analyses, native state electrospray ionization mass spectrometry, UV-vis spectrophotometry, and molecular docking. The uncovered inhibitor, compound 72922413, was shown to be 9-hydroxy-3-[(5-hydroxy-1-oxa-9-azaspiro[5.5]undec-9-yl)carbonyl]-4H-pyrido[1,2-a]pyrimidin-4-one.


Asunto(s)
Aprendizaje Automático , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Inhibidores de beta-Lactamasas , beta-Lactamasas , beta-Lactamasas/metabolismo , beta-Lactamasas/química , Inhibidores de beta-Lactamasas/farmacología , Inhibidores de beta-Lactamasas/química , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/enzimología , Escherichia coli/efectos de los fármacos , Escherichia coli/enzimología , Ensayos Analíticos de Alto Rendimiento
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