130077 20240122171020.0 doi 10.3390/ijms221810137 sideral 125805 ART-2021-125805 eng Salillas S. Universidad de Zaragoza (orcid)0000-0003-0195-5434 Selective targeting of human and animal pathogens of the helicobacter genus by flavodoxin inhibitors: Efficacy, synergy, resistance and mechanistic studies 2021 Antimicrobial resistant (AMR) bacteria constitute a global health concern. Helicobacter py-lori is a Gram-negative bacterium that infects about half of the human population and is a major cause of peptic ulcer disease and gastric cancer. Increasing resistance to triple and quadruple H. pylori eradication therapies poses great challenges and urges the development of novel, ideally narrow spectrum, antimicrobials targeting H. pylori. Here, we describe the antimicrobial spectrum of a family of nitrobenzoxadiazol-based antimicrobials initially discovered as inhibitors of flavodoxin: an essential H. pylori protein. Two groups of inhibitors are described. One group is formed by nar-row-spectrum compounds, highly specific for H. pylori, but ineffective against enterohepatic Helico-bacter species and other Gram-negative or Gram-positive bacteria. The second group includes ex-tended-spectrum antimicrobials additionally targeting Gram-positive bacteria, the Gram-negative Campylobacter jejuni, and most Helicobacter species, but not affecting other Gram-negative pathogens. To identify the binding site of the inhibitors in the flavodoxin structure, several H. pylori-flavodoxin variants have been engineered and tested using isothermal titration calorimetry. An initial study of the inhibitors capacity to generate resistances and of their synergism with antimicrobials commonly used in H. pylori eradication therapies is described. The narrow-spectrum inhibitors, which are ex-pected to affect the microbiota less dramatically than current antimicrobial drugs, offer an oppor-tunity to develop new and specific H. pylori eradication combinations to deal with AMR in H. pylori. On the other hand, the extended-spectrum inhibitors constitute a new family of promising antimi-crobials, with a potential use against AMR Gram-positive bacterial pathogens. © 2021 by the authors. Licensee MDPI, Basel, Switzerland. Access copy available to the general public Unrestricted info:eu-repo/grantAgreement/ES/DGA/E45-20R info:eu-repo/grantAgreement/ES/DGA/LMP30-18 info:eu-repo/grantAgreement/EC/H2020/801586/EU/International Doctoral Programme for Talent Attraction to the Campus of International Excellence of the Ebro Valley/IberusTalent This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No H2020 801586-IberusTalent info:eu-repo/grantAgreement/ES/MICINN/PID2019-107293GB-I00 info:eu-repo/semantics/openAccess by http://creativecommons.org/licenses/by/3.0/es/ 6.208 2021 BIOCHEMISTRY & MOLECULAR BIOLOGY 69 / 297 = 0.232 2021 Q1 T1 CHEMISTRY, MULTIDISCIPLINARY 50 / 179 = 0.279 2021 Q2 T1 1.176 2021 Computer Science Applications 2021 Q1 Inorganic Chemistry 2021 Q1 Spectroscopy 2021 Q1 Organic Chemistry 2021 Q1 Physical and Theoretical Chemistry 2021 Q1 Molecular Biology 2021 Q1 6.9 2021 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Galano-Frutos J.J. (orcid)0000-0002-1896-7805 Mahía A. (orcid)0000-0002-8839-6796 Maity R. Universidad de Zaragoza (orcid)0000-0003-4058-2888 Conde-Giménez M. (orcid)0000-0003-4358-9110 Anoz-Carbonell E. Universidad de Zaragoza (orcid)0000-0002-6649-9153 Berlamont H. Velazquez-Campoy A. Universidad de Zaragoza (orcid)0000-0001-5702-4538 Touati E. Mamat U. Schaible U.E. Gálvez J.A. Universidad de Zaragoza (orcid)0000-0002-4972-7476 Díaz-de-Villegas M.D. (orcid)0000-0001-9033-8459 Haesebrouck F. Aínsa J.A. Universidad de Zaragoza (orcid)0000-0003-2076-844X Sancho J. Universidad de Zaragoza (orcid)0000-0002-2879-9200 1011 630 Universidad de Zaragoza Dpto. Microb.Ped.Radio.Sal.Pú. Área Microbiología 2013 765 Universidad de Zaragoza Dpto. Química Orgánica Área Química Orgánica 1002 060 Universidad de Zaragoza Dpto. Bioq.Biolog.Mol. Celular Área Bioquímica y Biolog.Mole. 22, 18 (2021), 221810137 [25 pp.] Int. j. mol. sci. International Journal of Molecular Sciences 1661-6596 3757476 http://zaguan.unizar.es/record/130077/files/texto_completo.pdf Versión publicada 3058458 http://zaguan.unizar.es/record/130077/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:130077 articulos driver 2024-01-22-15:25:39 ARTICLE