Selective targeting of human and animal pathogens of the helicobacter genus by flavodoxin inhibitors: Efficacy, synergy, resistance and mechanistic studies

Salillas S. (Universidad de Zaragoza) ; Galano-Frutos J.J. ; Mahía A. ; Maity R. (Universidad de Zaragoza) ; Conde-Giménez M. ; Anoz-Carbonell E. (Universidad de Zaragoza) ; Berlamont H. ; Velazquez-Campoy A. (Universidad de Zaragoza) ; Touati E. ; Mamat U. ; Schaible U.E. ; Gálvez J.A. (Universidad de Zaragoza) ; Díaz-de-Villegas M.D. ; Haesebrouck F. ; Aínsa J.A. (Universidad de Zaragoza) ; Sancho J. (Universidad de Zaragoza)

Resumen: 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.

Idioma: Inglés

DOI: 10.3390/ijms221810137

Año: 2021

Publicado en: International Journal of Molecular Sciences 22, 18 (2021), 221810137 [25 pp.]
ISSN: 1661-6596

Factor impacto JCR: 6.208 (2021)

Categ. JCR: BIOCHEMISTRY & MOLECULAR BIOLOGY rank: 69 / 297 = 0.232 (2021) - Q1 - T1
Categ. JCR: CHEMISTRY, MULTIDISCIPLINARY rank: 50 / 179 = 0.279 (2021) - Q2 - T1

Factor impacto CITESCORE: 6.9 - Computer Science (Q1) - Chemical Engineering (Q1) - Medicine (Q1) - Biochemistry, Genetics and Molecular Biology (Q2)

Factor impacto SCIMAGO: 1.176 - Computer Science Applications (Q1) - Inorganic Chemistry (Q1) - Spectroscopy (Q1) - Organic Chemistry (Q1) - Physical and Theoretical Chemistry (Q1) - Molecular Biology (Q1)

Financiación: info:eu-repo/grantAgreement/ES/DGA/E45-20R
Financiación: info:eu-repo/grantAgreement/ES/DGA/LMP30-18
Financiación: 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
Financiación: info:eu-repo/grantAgreement/ES/MICINN/PID2019-107293GB-I00

Tipo y forma: Article (Published version)

Área (Departamento): Área Microbiología (Dpto. Microb.Ped.Radio.Sal.Pú.)
Área (Departamento): Área Química Orgánica (Dpto. Química Orgánica)
Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)