title: Repurposing the anticancer drug mitomycin C for the treatment of persistent Acinetobacter baumannii infections.
abstract: Acinetobacter baumannii is an emergent opportunistic bacterial pathogen responsible for recalcitrant infections owing to its high intrinsic tolerance to most antibiotics; therefore, suitable strategies to treat these infections are needed. One plausible approach is the repurposing of drugs that are already in use. Among them, anticancer drugs may be especially useful due their cytotoxic activities and ample similarities between bacterial infections and growing tumours. In this work, the effectiveness of four anticancer drugs on the growth of A. baumannii ATTC BAA-747 was evaluated, including the antimetabolite 5-fluorouracil and three DNA crosslinkers, namely cisplatin, mitomycin C (MMC) and merphalan. MMC was the most effective drug, having a minimum inhibitory concentration for 50% of growth in Luria-Bertani medium at ca. 7 µg/mL and completely inhibiting growth at 25 µg/mL. Hence, MMC was tested against a panel of 21 clinical isolates, including 18 multidrug-resistant (MDR) isolates, 3 of which were sensitive only to colistin. The minimum inhibitory concentrations and minimum bactericidal concentrations of MMC in all tested strains were found to be similar to those of A. baumannii ATCC BAA-747, and MMC also effectively killed stationary-phase, persister and biofilm cells. Moreover, MMC was able to increase survival of the insect larvae Galleria mellonella against an otherwise lethal A. baumannii infection from 0% to ≥53% for the antibiotic-sensitive A. baumannii ATCC BAA-747 strain and the MDR strains A560 and A578. Therefore, MMC is highly effective at killing the emergent opportunistic pathogen A. baumannii.
authors.affiliation: Departamento de Microbiología y Parasitología, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Av. Universidad 3000, Coyoacán, Copilco Universidad, 04510 Mexico City, DF, Mexico.
authors.forename: Martha Yumiko
authors.initials: MY
authors.lastname: Cruz-Muñiz
authors.affiliation: Departamento de Microbiología y Parasitología, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Av. Universidad 3000, Coyoacán, Copilco Universidad, 04510 Mexico City, DF, Mexico; Laboratorio de Infectología, Instituto Nacional de Rehabilitación, Mexico City, Mexico.
authors.forename: Luis Esau
authors.initials: LE
authors.lastname: López-Jacome
authors.affiliation: Laboratorio de Infectología, Instituto Nacional de Rehabilitación, Mexico City, Mexico.
authors.forename: Melissa
authors.initials: M
authors.lastname: Hernández-Durán
authors.affiliation: Laboratorio de Infectología, Instituto Nacional de Rehabilitación, Mexico City, Mexico.
authors.forename: Rafael
authors.initials: R
authors.lastname: Franco-Cendejas
authors.affiliation: Departamento de Biología Celular y del Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), 04510 Mexico City, DF, Mexico.
authors.forename: Paula
authors.initials: P
authors.lastname: Licona-Limón
authors.affiliation: Departamento de Biología Celular y del Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), 04510 Mexico City, DF, Mexico.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Ramos-Balderas
authors.affiliation: Instituto de Química, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico.
authors.forename: Mariano
authors.initials: M
authors.lastname: Martinéz-Vázquez
authors.affiliation: Departamento de Bioquímica, Instituto Nacional de Cardiología, Mexico City, Mexico.
authors.forename: Javier A
authors.initials: JA
authors.lastname: Belmont-Díaz
authors.affiliation: Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA, USA.
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Wood
authors.affiliation: Departamento de Microbiología y Parasitología, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Av. Universidad 3000, Coyoacán, Copilco Universidad, 04510 Mexico City, DF, Mexico. Electronic address: rgarc@bq.unam.mx.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: García-Contreras
mesh_terms: D000151:Acinetobacter Infections / Q000188:drug therapy / Q000382:microbiology; D040981:Acinetobacter baumannii / Q000187:drug effects* / Q000254:growth & development; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology; D004195:Disease Models, Animal; D058492:Drug Repositioning; D005472:Fluorouracil / Q000494:pharmacology; D007814:Larva / Q000382:microbiology; D007915:Lepidoptera / Q000382:microbiology; D008558:Melphalan / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D016685:Mitomycin / Q000008:administration & dosage / Q000494:pharmacology*; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D016685:Mitomycin; D002945:Cisplatin; D008558:Melphalan; D005472:Fluorouracil
keywords: Antibiotic resistance; Anticancer drugs; Drug repurposing