Machine Learning Models Identify Inhibitors of New Delhi Metallo-ß-lactamase.
J Chem Inf Model
; 64(10): 3977-3991, 2024 May 27.
Article
de En
| MEDLINE
| ID: mdl-38727192
ABSTRACT
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.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Bêta-Lactamases
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Tests de sensibilité microbienne
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Simulation de docking moléculaire
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Inhibiteurs des bêta-lactamases
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Apprentissage machine
Langue:
En
Journal:
J Chem Inf Model
/
J. chem. inf. model
/
Journal of chemical information and modeling
Sujet du journal:
INFORMATICA MEDICA
/
QUIMICA
Année:
2024
Type de document:
Article
Pays d'affiliation:
États-Unis d'Amérique
Pays de publication:
États-Unis d'Amérique