Abstract
The lack of therapeutic options to treat infections caused by multidrug-resistant (MDR) pathogens, especially Gram-negative bacteria, is apparent. Therefore, it is imperative to develop new strategies to address the problem of antimicrobial resistance. Repurposing non-antibiotic commercial drugs for antimicrobial therapy presents a viable option. We screened six anticancer drugs for their potential use in antimicrobial therapy. Here, we provide in vitro evidence that suggests feasibility to repurpose the anticancer drug mitomycin C against MDR Gram-negative bacteria. We also demonstrated that mitomycin C, etoposide and doxorubicin were affected by drug efflux in Pseudomonas aeruginosa. In combination with a tobramycin-ciprofloxacin antibiotic hybrid (TOB-CIP), the antibacterial activity of mitomycin C was enhanced against MDR clinical isolates of P. aeruginosa, Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae. In fact, 4 μg/mL (3 μM) TOB-CIP reduced the minimum inhibitory concentration of mitomycin C to ≤1 μg/mL against MDR Gram-negative bacteria, except A. baumannii. We showed that synergy was inherent to TOB-CIP and that neither tobramycin nor ciprofloxacin individually synergized with mitomycin C. Our finding supports identifying adjuvant partners for mitomycin C, such as TOB-CIP, to enhance suitability for antimicrobial therapy.
Highlights
There is a dire need to develop new strategies that can supplement our dwindling antibiotic armamentarium to address the growing threat of antimicrobial resistance (Luepke et al, 2017; Domalaon et al, 2018a; Koulenti et al, 2018)
We found that the anticancer agent mitomycin C possessed potent antibacterial activity against Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae, while limited activity was observed against Acinetobacter baumannii
The antibacterial activity of six anticancer agents were assessed against antibiotic susceptible strains (ASS) of P. aeruginosa, A. baumannii, and E. coli using microdilution broth assay and activities were reported as their Minimum inhibitory concentration (MIC) or the minimum concentration of the agents to prevent visible bacterial growth
Summary
Repurposing non-antibiotic drugs for antimicrobial therapy offers a cost- and time-efficient method of discovery (Rangel-Vega et al, 2015; Soo et al, 2017; Polamreddy and Gattu, 2018; Cavalla, 2019). This is advantageous since the agents under study have wellcharacterized pharmacokinetic parameters and have undergone the rigorous process of safety evaluation from health agencies such as the United States’ Food and Drug Administration (FDA) (Gns et al, 2019). Several non-antibiotic drugs have been described in the literature to display potential use for the treatment of MDR Gram-negative bacterial infections (Hennessy et al, 2016; Cheng et al, 2018; Lee and O’Neill, 2018; Domalaon et al, 2019)
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