Antimicrobial combinations against Helicobacter pylori including benzoxadiazol-based flavodoxin inhibitors: in vitro characterization

Beyria, Lilha ; Gourbeyre, Ophelie ; Salillas, Sandra (Universidad de Zaragoza) ; Mahía, Alejandro ; Díaz de Villegas, María Dolores ; Aínsa, José Antonio (Universidad de Zaragoza) ; Sancho, Javier (Universidad de Zaragoza) ; Bousquet-Mélou, Alain ; Ferran, Aude A.

Resumen: Antimicrobial resistance of Helicobacter pylori (Hp) threatens currently available treatment regimens and prompts the development of antimicrobial drugs against new bacterial targets. One such class of drugs is Hp-flavodoxin (Hp-fld) inhibitors, which target an essential metabolic pathway in Hp. The aim of this study was to characterize the effects of these inhibitors against Hp over time when used alone or combined with conventional antibiotics. Four benzoxadiazol-based fld inhibitors were initially tested for their in vitro potency, with compound IV displaying the highest efficacy. This compound was then combined with clarithromycin, metronidazole, amoxicillin, levofloxacin, and rifampicin in further experiments. Checkerboard assays indicated that compound IV exhibited additive activity when combined with these antibiotics. The study further investigated the time course of antibacterial effects by exposing a high inoculum of Hp to compound IV and each antibiotic, alone or in combination. At just four times the minimum inhibitory concentration, compound IV demonstrated bactericidal effects within 6 h. However, the regrowth of bacteria occurred between 24 and 48 h of exposure. Similar patterns of killing followed by regrowth were observed for conventional antibiotics alone. However, the addition of compound IV to the antibiotics clearly limited regrowth over 72 h. These findings suggest that compound IV can effectively eliminate spontaneous mutants that are resistant to conventional antibiotics or prevent new mutations during drug exposure. Hp-fld inhibitors, such as compound IV, hold promise as new drugs to be integrated into Hp infection treatment, potentially reducing the development of resistance and shortening the duration of treatment.

Idioma: Inglés

DOI: 10.1128/spectrum.02623-23

Año: 2024

Publicado en: Microbiology Spectrum 12, 1 (2024), e02623-23 [12 pp.]
ISSN: 2165-0497

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

Tipo y forma: Artículo (Versión definitiva)

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