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In vitro synergy screens of FDA-approved drugs reveal novel zidovudine- and azithromycin-based combinations with last-line antibiotics against Klebsiella pneumoniae.
Gómara-Lomero, Marta; López-Calleja, Ana Isabel; Rezusta, Antonio; Aínsa, José Antonio; Ramón-García, Santiago.
Afiliação
  • Gómara-Lomero M; Department of Microbiology. Faculty of Medicine, University of Zaragoza, C/ Domingo Miral S/N, 50009, Zaragoza, Spain. mgomara@unizar.es.
  • López-Calleja AI; Servicio de Microbiología, Hospital Universitario Miguel Servet, Zaragoza, Spain.
  • Rezusta A; Servicio de Microbiología, Hospital Universitario Miguel Servet, Zaragoza, Spain.
  • Aínsa JA; Department of Microbiology. Faculty of Medicine, University of Zaragoza, C/ Domingo Miral S/N, 50009, Zaragoza, Spain.
  • Ramón-García S; CIBER Respiratory Diseases, Carlos III Health Institute, Madrid, Spain.
Sci Rep ; 13(1): 14429, 2023 09 02.
Article em En | MEDLINE | ID: mdl-37660210
ABSTRACT
Treatment of infections caused by multi-drug resistant (MDR) enterobacteria remains challenging due to the limited therapeutic options available. Drug repurposing could accelerate the development of new urgently needed successful interventions. This work aimed to identify and characterise novel drug combinations against Klebsiella pneumoniae based on the concepts of synergy and drug repurposing. We first performed a semi-qualitative high-throughput synergy screen (sHTSS) with tigecycline, colistin and fosfomycin (last-line antibiotics against MDR Enterobacteriaceae) against a FDA-library containing 1430 clinically approved drugs; a total of 109 compounds potentiated any of the last-line antibiotics. Selected hits were further validated by secondary checkerboard (CBA) and time-kill (TKA) assays, obtaining 15.09% and 65.85% confirmation rates, respectively. Accordingly, TKA were used for synergy classification based on determination of bactericidal activities at 8, 24 and 48 h, selecting 27 combinations against K. pneumoniae. Among them, zidovudine or azithromycin combinations with last-line antibiotics were further evaluated by TKA against a panel of 12 MDR/XDR K. pneumoniae strains, and their activities confronted with those clinical combinations currently used for MDR enterobacteria treatment; these combinations showed better bactericidal activities than usual treatments without added cytotoxicity. Our studies show that sHTSS paired to TKA are powerful tools for the identification and characterisation of novel synergistic drug combinations against K. pneumoniae. Further pre-clinical studies might support the translational potential of zidovudine- and azithromycin-based combinations for the treatment of these infections.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Azitromicina / Antibacterianos Tipo de estudo: Qualitative_research Idioma: En Revista: Sci Rep Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Espanha

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Azitromicina / Antibacterianos Tipo de estudo: Qualitative_research Idioma: En Revista: Sci Rep Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Espanha