000145165 001__ 145165
000145165 005__ 20241003094705.0
000145165 0247_ $$2doi$$a10.3390/ijms251810175
000145165 0248_ $$2sideral$$a139972
000145165 037__ $$aART-2024-139972
000145165 041__ $$aeng
000145165 100__ $$aCasado, Javier
000145165 245__ $$aNovel drug-like HsrA inhibitors exhibit potent narrow-spectrum antimicrobial activities against Helicobacter pylori
000145165 260__ $$c2024
000145165 5060_ $$aAccess copy available to the general public$$fUnrestricted
000145165 5203_ $$aHelicobacter 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.
000145165 536__ $$9info:eu-repo/grantAgreement/ES/DGA/B25-20R$$9info:eu-repo/grantAgreement/ES/DGA/B25-23R$$9info:eu-repo/grantAgreement/ES/DGA/E35-20R$$9info:eu-repo/grantAgreement/ES/ISCIII/PI21-00098
000145165 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000145165 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000145165 700__ $$0(orcid)0009-0005-3815-865X$$aOliván-Muro, Irene$$uUniversidad de Zaragoza
000145165 700__ $$0(orcid)0000-0002-0036-6630$$aAlgarate, Sonia
000145165 700__ $$aChueca, Eduardo
000145165 700__ $$0(orcid)0000-0003-0195-5434$$aSalillas, Sandra$$uUniversidad de Zaragoza
000145165 700__ $$0(orcid)0000-0001-5702-4538$$aVelázquez-Campoy, Adrián$$uUniversidad de Zaragoza
000145165 700__ $$0(orcid)0000-0001-5813-3445$$aPiazuelo, Elena$$uUniversidad de Zaragoza
000145165 700__ $$0(orcid)0000-0001-8644-4574$$aFillat, María F.$$uUniversidad de Zaragoza
000145165 700__ $$0(orcid)0000-0002-2879-9200$$aSancho, Javier$$uUniversidad de Zaragoza
000145165 700__ $$0(orcid)0000-0001-5932-2889$$aLanas, Ángel$$uUniversidad de Zaragoza
000145165 700__ $$0(orcid)0000-0002-0531-0943$$aGonzález, Andrés$$uUniversidad de Zaragoza
000145165 7102_ $$11011$$2630$$aUniversidad de Zaragoza$$bDpto. Microb.Ped.Radio.Sal.Pú.$$cÁrea Microbiología
000145165 7102_ $$11012$$2410$$aUniversidad de Zaragoza$$bDpto. Farmac.Fisiol.y Med.L.F.$$cÁrea Fisiología
000145165 7102_ $$11007$$2610$$aUniversidad de Zaragoza$$bDpto. Medicina, Psiqu. y Derm.$$cArea Medicina
000145165 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000145165 773__ $$g25, 18 (2024), 10175 [27 pp.]$$pInt. j. mol. sci.$$tInternational Journal of Molecular Sciences$$x1661-6596
000145165 787__ $$tTranscriptomic analysis of Helicobacter pylori 26695 exposed to lethal concentration of a bactericidal inhibitor of the essential response regulator HsrA$$wArrayExpress E-MTAB-14255
000145165 8564_ $$s4361044$$uhttps://zaguan.unizar.es/record/145165/files/texto_completo.pdf$$yVersión publicada
000145165 8564_ $$s2665071$$uhttps://zaguan.unizar.es/record/145165/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000145165 909CO $$ooai:zaguan.unizar.es:145165$$particulos$$pdriver
000145165 951__ $$a2024-10-03-08:56:14
000145165 980__ $$aARTICLE