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Rational design of 1H-pyrrole-2-carboxylic acid inhibitors of NDM-1 metallo-β-lactamase restoring β-lactam efficacy against resistant Enterobacteralesстатья
Статья опубликована в высокорейтинговом журнале
Информация о цитировании статьи получена из
Scopus
Статья опубликована в журнале из списка Web of Science и/или Scopus
Дата последнего поиска статьи во внешних источниках: 23 января 2026 г.
- Авторы: Shkuratova Tatiana S., Rychev Kirill V., Grigorenko Vitaly G., Andreeva Irina P., Grammatikova Natalia E., Tikhomirov Alexander S., Egorov Alexey M., Shchekotikhin Andrey E.
- Журнал: European Journal of Medicinal Chemistry
- Том: 302
- Год издания: 2026
- Издательство: Elsevier BV
- Местоположение издательства: Netherlands
- Первая страница: 118376
- Последняя страница: 118387
- DOI: 10.1016/j.ejmech.2025.118376
- Аннотация: Antimicrobial resistance mediated by metallo-β-lactamases (MBLs) represents a critical challenge for the efficacy of β-lactam antibiotics. Here, we report the design, synthesis, and evaluation of a novel class of 3,5-diaryl-1H-pyrrole-2-carboxylic acids as potent New Delhi metallo-β-lactamase (NDM)-type MBL inhibitors. Guided by molecular modeling and structure–activity relationship studies, the pyrrole scaffold was optimized through systematic modifications of the phenyl rings at position 3 and 5 of pyrrole core, yielding derivatives with low-nanomolar IC50 values against NDM-1. Key interactions involve coordination of the pyrrole carboxyl groups with Zn2+ ions and hydrogen bonding with active-site residues, supporting enhanced binding and inhibitory potency. Lead compounds restored the activity of cefepime and meropenem against NDM-positive E. coli and K. pneumoniae strains, while triple combinations with serine β-lactamase inhibitors further enhanced antimicrobial efficacy. These results highlight 1H-pyrrole-2-carboxylic acids as a versatile scaffold for MBL inhibition and provide a rational framework for the development of therapeutics against multidrug-resistant pathogens.
- Добавил в систему: Григоренко Виталий Георгиевич
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