The aims of this study were (i) to determine if the combination of mitomycin C with pentamidine or existing antibiotics resulted in enhanced efficacy versus infections with MDR in vivo; and (ii) to determine if the doses of mitomycin C and pentamidine in combination can be reduced to levels that are non-toxic in humans but still retain antibacterial activity. Resistant clinical isolates of , a mutant strain over-expressing the MexAB-OprM resistance nodulation division (RND) efflux pump and a strain with three RND pumps deleted, were used. MIC assays indicated that all strains were sensitive to mitomycin C, but deletion of three RND pumps resulted in hypersensitivity and over-expression of MexAB-OprM caused some resistance. These results imply that mitomycin C is a substrate of the RND efflux pumps. Mitomycin C monotherapy successfully treated infected larvae, albeit at doses too high for human administration. Checkerboard and time-kill assays showed that the combination of mitomycin C with pentamidine, or the antibiotic gentamicin, resulted in synergistic inhibition of most strains in vitro. In vivo, administration of a combination therapy of mitomycin C with pentamidine, or gentamicin, to larvae infected with resulted in enhanced efficacy compared with monotherapies for the majority of MDR clinical isolates. Notably, the therapeutic benefit conferred by the combination therapy occurred with doses of mitomycin C close to those used in human medicine. Thus, repurposing mitomycin C in combination therapies to target MDR infections merits further investigation.
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http://dx.doi.org/10.3390/antibiotics13020177 | DOI Listing |
Antibiotics (Basel)
February 2024
Biomedical Sciences Research Complex, School of Biology, University of St Andrews, The North Haugh, St Andrews, Fife KY16 9ST, UK.
The aims of this study were (i) to determine if the combination of mitomycin C with pentamidine or existing antibiotics resulted in enhanced efficacy versus infections with MDR in vivo; and (ii) to determine if the doses of mitomycin C and pentamidine in combination can be reduced to levels that are non-toxic in humans but still retain antibacterial activity. Resistant clinical isolates of , a mutant strain over-expressing the MexAB-OprM resistance nodulation division (RND) efflux pump and a strain with three RND pumps deleted, were used. MIC assays indicated that all strains were sensitive to mitomycin C, but deletion of three RND pumps resulted in hypersensitivity and over-expression of MexAB-OprM caused some resistance.
View Article and Find Full Text PDFAntibiotics (Basel)
March 2023
Pharmaceutical Sciences Department, Faculty of Pharmacy, Al-Quds University, Jerusalem P.O. Box 20002, Palestine.
The necessity for the discovery of innovative antimicrobials to treat life-threatening diseases has increased as multidrug-resistant bacteria has spread. Due to antibiotics' availability over the counter in many nations, antibiotic resistance is linked to overuse, abuse, and misuse of these drugs. The World Health Organization (WHO) recognized 12 families of bacteria that present the greatest harm to human health, where options of antibiotic therapy are extremely limited.
View Article and Find Full Text PDFEur J Clin Microbiol Infect Dis
September 2020
Institute of Chemical Biology and Nanomedicine, State Key Laboratory of Chem/Biosensing and Chemometrics, Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, and Department of Chemistry, Hunan University, Changsha, 410082, China.
Pentamidine sensitizes FDA-approved antibiotics to combat Gram-negative pathogens. We screened 1374 FDA-approved non-antibiotics for their ability to be sensitized by pentamidine against Escherichia coli. We identified mitomycin C and mefloquine as potent hits effective against multiple drug-resistant, Gram-negative bacteria.
View Article and Find Full Text PDFMol Cancer Ther
August 2004
Department of Oncology, Faculty of Medicine, McGill University Health Centre/Montreal General Hospital, 1650 Avenue Cedar, Room 10-148, Montreal, Quebec, Canada H3G 1A4.
DNA repair mechanisms are crucial for the maintenance of genomic stability and are emerging as potential therapeutic targets for cancer. In this study, we report that the endo-exonuclease, a protein involved in the recombination repair process of the DNA double-stranded break pathway, is overexpressed in a variety of cancer cells and could represent an effective target for developing anticancer drugs. We identify a dicationic diarylfuran, pentamidine, which has been used clinically to treat opportunistic infections and is an inhibitor of the endo-exonuclease as determined by enzyme kinetic assay.
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