Novel drug-like HsrA inhibitors exhibit potent narrow-spectrum antimicrobial activities against Helicobacter pylori

Casado, Javier ; Oliván-Muro, Irene (Universidad de Zaragoza) ; Algarate, Sonia ; Chueca, Eduardo ; Salillas, Sandra (Universidad de Zaragoza) ; Velázquez-Campoy, Adrián (Universidad de Zaragoza) ; Piazuelo, Elena (Universidad de Zaragoza) ; Fillat, María F. (Universidad de Zaragoza) ; Sancho, Javier (Universidad de Zaragoza) ; Lanas, Ángel (Universidad de Zaragoza) ; González, Andrés (Universidad de Zaragoza)

Resumen: Helicobacter pylori infection constitutes a silent pandemic of global concern. In the last decades, the alarming increase in multidrug resistance evolved by this pathogen has led to a marked drop in the eradication rates of traditional therapies worldwide. By using a high-throughput screening strategy, in combination with in vitro DNA binding assays and antibacterial activity testing, we identified a battery of novel drug-like HsrA inhibitors with MIC values ranging from 0.031 to 4 mg/L against several antibiotic-resistant strains of H. pylori, and minor effects against both Gram-negative and Gram-positive species of human microbiota. The most potent anti-H. pylori candidate demonstrated a high therapeutic index, an additive effect in combination with metronidazole and clarithromycin as well as a strong antimicrobial action against Campylobacter jejuni, another clinically relevant pathogen of phylum Campylobacterota. Transcriptomic analysis suggests that the in vivo inhibition of HsrA triggers lethal global disturbances in H. pylori physiology including the arrest of protein biosynthesis, malfunction of respiratory chain, detriment in ATP generation, and oxidative stress. The novel drug-like HsrA inhibitors described here constitute valuable candidates to a new family of narrow-spectrum antibiotics that allow overcoming the current resistome, protecting from dysbiosis, and increasing therapeutic options for novel personalized treatments against H. pylori.

Idioma: Inglés

DOI: 10.3390/ijms251810175

Año: 2024

Publicado en: International Journal of Molecular Sciences 25, 18 (2024), 10175 [27 pp.]
ISSN: 1661-6596

Financiación: info:eu-repo/grantAgreement/ES/DGA/B25-20R
Financiación: info:eu-repo/grantAgreement/ES/DGA/B25-23R
Financiación: info:eu-repo/grantAgreement/ES/DGA/E35-20R
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/PI21-00098

Tipo y forma: Article (Published version)

Área (Departamento): Área Microbiología (Dpto. Microb.Ped.Radio.Sal.Pú.)
Área (Departamento): Área Fisiología (Dpto. Farmac.Fisiol.y Med.L.F.)
Área (Departamento): Area Medicina (Dpto. Medicina, Psiqu. y Derm.)
Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)

Dataset asociado: Transcriptomic analysis of Helicobacter pylori 26695 exposed to lethal concentration of a bactericidal inhibitor of the essential response regulator HsrA ( ArrayExpress E-MTAB-14255)