000127993 001__ 127993 000127993 005__ 20241125101201.0 000127993 0247_ $$2doi$$a10.1038/s41598-023-39647-9 000127993 0248_ $$2sideral$$a135103 000127993 037__ $$aART-2023-135103 000127993 041__ $$aeng 000127993 100__ $$aGómara-Lomero, Marta 000127993 245__ $$aIn vitro synergy screens of FDA-approved drugs reveal novel zidovudine- and azithromycin-based combinations with last-line antibiotics against Klebsiella pneumoniae 000127993 260__ $$c2023 000127993 5060_ $$aAccess copy available to the general public$$fUnrestricted 000127993 5203_ $$aTreatment 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. 000127993 536__ $$9info:eu-repo/grantAgreement/ES/DGA/B35-23R$$9info:eu-repo/grantAgreement/ES/DGA/LMP132-18 000127993 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/ 000127993 590__ $$a3.8$$b2023 000127993 592__ $$a0.9$$b2023 000127993 591__ $$aMULTIDISCIPLINARY SCIENCES$$b25 / 134 = 0.187$$c2023$$dQ1$$eT1 000127993 593__ $$aMultidisciplinary$$c2023$$dQ1 000127993 594__ $$a7.5$$b2023 000127993 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion 000127993 700__ $$aLópez-Calleja, Ana Isabel 000127993 700__ $$0(orcid)0000-0001-7294-245X$$aRezusta, Antonio 000127993 700__ $$0(orcid)0000-0003-2076-844X$$aAínsa, José Antonio$$uUniversidad de Zaragoza 000127993 700__ $$0(orcid)0000-0002-8480-0325$$aRamón-García, Santiago 000127993 7102_ $$11011$$2630$$aUniversidad de Zaragoza$$bDpto. Microb.Ped.Radio.Sal.Pú.$$cÁrea Microbiología 000127993 773__ $$g13, 1 (2023), 14429 [16 pp.]$$pSci. rep. (Nat. Publ. Group)$$tScientific reports (Nature Publishing Group)$$x2045-2322 000127993 8564_ $$s3745227$$uhttps://zaguan.unizar.es/record/127993/files/texto_completo.pdf$$yVersión publicada 000127993 8564_ $$s2188829$$uhttps://zaguan.unizar.es/record/127993/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada 000127993 909CO $$ooai:zaguan.unizar.es:127993$$particulos$$pdriver 000127993 951__ $$a2024-11-22-12:11:34 000127993 980__ $$aARTICLE