Selective Targeting of Human and Animal Pathogens of the Helicobacter Genus by Flavodoxin Inhibitors: Efficacy, Synergy, Resistance and Mechanistic Studies.

Autor: Salillas S; Biocomputation and Complex Systems Physics Institute (BIFI)-Joint Units: BIFI-IQFR (CSIC) and GBsC-CSIC, University of Zaragoza, 50018 Zaragoza, Spain.; Departamento de Bioquímica y Biología Molecular y Celular, Faculty of Science, University of Zaragoza, 50009 Zaragoza, Spain.; Aragon Health Research Institute (IIS Aragón), 50009 Zaragoza, Spain., Galano-Frutos JJ; Biocomputation and Complex Systems Physics Institute (BIFI)-Joint Units: BIFI-IQFR (CSIC) and GBsC-CSIC, University of Zaragoza, 50018 Zaragoza, Spain.; Departamento de Bioquímica y Biología Molecular y Celular, Faculty of Science, University of Zaragoza, 50009 Zaragoza, Spain.; Aragon Health Research Institute (IIS Aragón), 50009 Zaragoza, Spain., Mahía A; Biocomputation and Complex Systems Physics Institute (BIFI)-Joint Units: BIFI-IQFR (CSIC) and GBsC-CSIC, University of Zaragoza, 50018 Zaragoza, Spain.; Departamento de Bioquímica y Biología Molecular y Celular, Faculty of Science, University of Zaragoza, 50009 Zaragoza, Spain.; Aragon Health Research Institute (IIS Aragón), 50009 Zaragoza, Spain., Maity R; Biocomputation and Complex Systems Physics Institute (BIFI)-Joint Units: BIFI-IQFR (CSIC) and GBsC-CSIC, University of Zaragoza, 50018 Zaragoza, Spain.; Departamento de Bioquímica y Biología Molecular y Celular, Faculty of Science, University of Zaragoza, 50009 Zaragoza, Spain.; Aragon Health Research Institute (IIS Aragón), 50009 Zaragoza, Spain., Conde-Giménez M; Biocomputation and Complex Systems Physics Institute (BIFI)-Joint Units: BIFI-IQFR (CSIC) and GBsC-CSIC, University of Zaragoza, 50018 Zaragoza, Spain.; Departamento de Bioquímica y Biología Molecular y Celular, Faculty of Science, University of Zaragoza, 50009 Zaragoza, Spain.; Aragon Health Research Institute (IIS Aragón), 50009 Zaragoza, Spain., Anoz-Carbonell E; Biocomputation and Complex Systems Physics Institute (BIFI)-Joint Units: BIFI-IQFR (CSIC) and GBsC-CSIC, University of Zaragoza, 50018 Zaragoza, Spain.; Departamento de Bioquímica y Biología Molecular y Celular, Faculty of Science, University of Zaragoza, 50009 Zaragoza, Spain.; Departamento de Microbiología, Pediatría, Radiología y Salud Pública, Faculty of Medicine, University of Zaragoza, 50009 Zaragoza, Spain., Berlamont H; Department of Pathobiology, Pharmacology and Zoological Medicine, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, B9820 Merelbeke, Belgium., Velazquez-Campoy A; Biocomputation and Complex Systems Physics Institute (BIFI)-Joint Units: BIFI-IQFR (CSIC) and GBsC-CSIC, University of Zaragoza, 50018 Zaragoza, Spain.; Departamento de Bioquímica y Biología Molecular y Celular, Faculty of Science, University of Zaragoza, 50009 Zaragoza, Spain.; Aragon Health Research Institute (IIS Aragón), 50009 Zaragoza, Spain.; ARAID Foundation, Government of Aragon, 50018 Zaragoza, Spain.; CIBER de Enfermedades Hepáticas y Digestivas CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain., Touati E; Unit of Helicobacter Pathogenesis, CNRS UMR2001, Department of Microbiology, Institut Pasteur, 25-28 Rue du Dr. Roux, 75724 Paris, France., Mamat U; Cellular Microbiology, Program Area Infections, Research Center Borstel, Leibniz Lung Center, 23845 Borstel, Germany., Schaible UE; Cellular Microbiology, Program Area Infections, Research Center Borstel, Leibniz Lung Center, 23845 Borstel, Germany., Gálvez JA; Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), CSIC-Departamento de Química Orgánica, Faculty of Science, University of Zaragoza, 50009 Zaragoza, Spain., Díaz-de-Villegas MD; Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), CSIC-Departamento de Química Orgánica, Faculty of Science, University of Zaragoza, 50009 Zaragoza, Spain., Haesebrouck F; Department of Pathobiology, Pharmacology and Zoological Medicine, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, B9820 Merelbeke, Belgium., Aínsa JA; Biocomputation and Complex Systems Physics Institute (BIFI)-Joint Units: BIFI-IQFR (CSIC) and GBsC-CSIC, University of Zaragoza, 50018 Zaragoza, Spain.; Aragon Health Research Institute (IIS Aragón), 50009 Zaragoza, Spain.; Departamento de Microbiología, Pediatría, Radiología y Salud Pública, Faculty of Medicine, University of Zaragoza, 50009 Zaragoza, Spain.; CIBER de Enfermedades Respiratorias-CIBERES, Instituto de Salud Carlos III, 28029 Madrid, Spain., Sancho J; Biocomputation and Complex Systems Physics Institute (BIFI)-Joint Units: BIFI-IQFR (CSIC) and GBsC-CSIC, University of Zaragoza, 50018 Zaragoza, Spain.; Departamento de Bioquímica y Biología Molecular y Celular, Faculty of Science, University of Zaragoza, 50009 Zaragoza, Spain.; Aragon Health Research Institute (IIS Aragón), 50009 Zaragoza, Spain.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2021 Sep 20; Vol. 22 (18). Date of Electronic Publication: 2021 Sep 20.
DOI: 10.3390/ijms221810137
Abstrakt: Antimicrobial resistant (AMR) bacteria constitute a global health concern. Helicobacter pylori 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 narrow-spectrum compounds, highly specific for H. pylori , but ineffective against enterohepatic Helicobacter species and other Gram-negative or Gram-positive bacteria. The second group includes extended-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 expected to affect the microbiota less dramatically than current antimicrobial drugs, offer an opportunity 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 antimicrobials, with a potential use against AMR Gram-positive bacterial pathogens.
Databáze: MEDLINE
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