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Repurposing the anticancer drug mitomycin C for the treatment of persistent Acinetobacter baumannii infections
Martha Yumiko Cruz-Muñiz1, Luis Esau López-Jacome2, Melissa Hernández-Durán3
1Departamento de Microbiología y Parasitología, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Av. Universidad 3000, Coyoacán, Copilco Universidad, 04510 Mexico City, DF, Mexico.
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.
Insights
Anticancer drug mitomycin C (MMC) effectively combats multidrug-resistant Acinetobacter baumannii infections. MMC shows efficacy against various bacterial forms and improves survival in an insect model, offering a promising treatment strategy.
Area of Science:
- Microbiology and Infectious Diseases
- Antimicrobial Resistance
- Drug Repurposing
Background:
- Acinetobacter baumannii is a significant opportunistic pathogen causing difficult-to-treat infections due to high antibiotic tolerance.
- There is a critical need for novel therapeutic strategies against recalcitrant A. baumannii infections.
- Anticancer drugs, with their cytotoxic properties, are potential candidates for repurposing against bacterial pathogens.
Purpose of the Study:
- To evaluate the efficacy of four anticancer drugs against Acinetobacter baumannii.
- To identify the most effective anticancer drug for treating A. baumannii infections.
- To assess the drug's activity against multidrug-resistant strains and different bacterial cell states.
Main Methods:
- In vitro testing of four anticancer drugs (5-fluorouracil, cisplatin, mitomycin C, merphalan) against A. baumannii ATCC BAA-747.
- Determination of minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations (MBC) for mitomycin C (MMC).
- Evaluation of MMC's efficacy against 21 clinical isolates (including 18 multidrug-resistant strains), stationary-phase, persister, and biofilm cells.
- In vivo assessment using the Galleria mellonella insect larvae model to determine survival rates.
Main Results:
- Mitomycin C (MMC) demonstrated the highest efficacy, with MIC50 at ~7 µg/mL and complete growth inhibition at 25 µg/mL.
- MMC exhibited consistent MIC and MBC values across all tested A. baumannii strains, including multidrug-resistant isolates.
- MMC effectively eradicated stationary-phase, persister, and biofilm cells.
- In the Galleria mellonella model, MMC significantly increased survival rates against A. baumannii infection.
Conclusions:
- Mitomycin C is a potent agent against Acinetobacter baumannii, including multidrug-resistant strains.
- MMC's effectiveness extends to various bacterial growth phases and forms, such as biofilms.
- Drug repurposing of mitomycin C presents a promising therapeutic avenue for treating challenging A. baumannii infections.
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