Novel Polymyxin Combination With Antineoplastic Mitotane Improved the Bacterial Killing Against Polymyxin-Resistant Multidrug-Resistant Gram-Negative Pathogens
Due to limited new antibiotics, polymyxins are increasingly used to treat multidrug-resistant (MDR) Gram-negative bacteria, in particular carbapenem-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae. Unfortunately, polymyxin monotherapy has led to the emergence of...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-04-01
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| Series: | Frontiers in Microbiology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fmicb.2018.00721/full |
| _version_ | 1818364215300194304 |
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| author | Thien B. Tran Thien B. Tran Jiping Wang Jiping Wang Yohei Doi Tony Velkov Tony Velkov Phillip J. Bergen Phillip J. Bergen Jian Li |
| author_facet | Thien B. Tran Thien B. Tran Jiping Wang Jiping Wang Yohei Doi Tony Velkov Tony Velkov Phillip J. Bergen Phillip J. Bergen Jian Li |
| author_sort | Thien B. Tran |
| collection | DOAJ |
| description | Due to limited new antibiotics, polymyxins are increasingly used to treat multidrug-resistant (MDR) Gram-negative bacteria, in particular carbapenem-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae. Unfortunately, polymyxin monotherapy has led to the emergence of resistance. Polymyxin combination therapy has been demonstrated to improve bacterial killing and prevent the emergence of resistance. From a preliminary screening of an FDA drug library, we identified antineoplastic mitotane as a potential candidate for combination therapy with polymyxin B against polymyxin-resistant Gram-negative bacteria. Here, we demonstrated that the combination of polymyxin B with mitotane enhances the in vitro antimicrobial activity of polymyxin B against 10 strains of A. baumannii, P. aeruginosa, and K. pneumoniae, including polymyxin-resistant MDR clinical isolates. Time-kill studies showed that the combination of polymyxin B (2 mg/L) and mitotane (4 mg/L) provided superior bacterial killing against all strains during the first 6 h of treatment, compared to monotherapies, and prevented regrowth and emergence of polymyxin resistance in the polymyxin-susceptible isolates. Electron microscopy imaging revealed that the combination potentially affected cell division in A. baumannii. The enhanced antimicrobial activity of the combination was confirmed in a mouse burn infection model against a polymyxin-resistant A. baumannii isolate. As mitotane is hydrophobic, it was very likely that the synergistic killing of the combination resulted from that polymyxin B permeabilized the outer membrane of the Gram-negative bacteria and allowed mitotane to enter bacterial cells and exert its antimicrobial effect. These results have important implications for repositioning non-antibiotic drugs for antimicrobial purposes, which may expedite the discovery of novel therapies to combat the rapid emergence of antibiotic resistance. |
| first_indexed | 2024-12-13T22:00:49Z |
| format | Article |
| id | doaj.art-6a153ac8f6bd432db82992b8a284acb1 |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-12-13T22:00:49Z |
| publishDate | 2018-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-6a153ac8f6bd432db82992b8a284acb12022-12-21T23:30:00ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2018-04-01910.3389/fmicb.2018.00721324424Novel Polymyxin Combination With Antineoplastic Mitotane Improved the Bacterial Killing Against Polymyxin-Resistant Multidrug-Resistant Gram-Negative PathogensThien B. Tran0Thien B. Tran1Jiping Wang2Jiping Wang3Yohei Doi4Tony Velkov5Tony Velkov6Phillip J. Bergen7Phillip J. Bergen8Jian Li9Monash Biomedicine Discovery Institute, Department of Microbiology, School of Biomedical Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, AustraliaDrug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, AustraliaMonash Biomedicine Discovery Institute, Department of Microbiology, School of Biomedical Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, AustraliaDrug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, AustraliaDivision of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, United StatesDrug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, AustraliaDepartment of Pharmacology and Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC, AustraliaDrug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, AustraliaCentre for Medicine Use and Safety, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, AustraliaMonash Biomedicine Discovery Institute, Department of Microbiology, School of Biomedical Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, AustraliaDue to limited new antibiotics, polymyxins are increasingly used to treat multidrug-resistant (MDR) Gram-negative bacteria, in particular carbapenem-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae. Unfortunately, polymyxin monotherapy has led to the emergence of resistance. Polymyxin combination therapy has been demonstrated to improve bacterial killing and prevent the emergence of resistance. From a preliminary screening of an FDA drug library, we identified antineoplastic mitotane as a potential candidate for combination therapy with polymyxin B against polymyxin-resistant Gram-negative bacteria. Here, we demonstrated that the combination of polymyxin B with mitotane enhances the in vitro antimicrobial activity of polymyxin B against 10 strains of A. baumannii, P. aeruginosa, and K. pneumoniae, including polymyxin-resistant MDR clinical isolates. Time-kill studies showed that the combination of polymyxin B (2 mg/L) and mitotane (4 mg/L) provided superior bacterial killing against all strains during the first 6 h of treatment, compared to monotherapies, and prevented regrowth and emergence of polymyxin resistance in the polymyxin-susceptible isolates. Electron microscopy imaging revealed that the combination potentially affected cell division in A. baumannii. The enhanced antimicrobial activity of the combination was confirmed in a mouse burn infection model against a polymyxin-resistant A. baumannii isolate. As mitotane is hydrophobic, it was very likely that the synergistic killing of the combination resulted from that polymyxin B permeabilized the outer membrane of the Gram-negative bacteria and allowed mitotane to enter bacterial cells and exert its antimicrobial effect. These results have important implications for repositioning non-antibiotic drugs for antimicrobial purposes, which may expedite the discovery of novel therapies to combat the rapid emergence of antibiotic resistance.http://journal.frontiersin.org/article/10.3389/fmicb.2018.00721/fullpolymyxinmitotanerepurposingcombination therapymultidrug-resistance |
| spellingShingle | Thien B. Tran Thien B. Tran Jiping Wang Jiping Wang Yohei Doi Tony Velkov Tony Velkov Phillip J. Bergen Phillip J. Bergen Jian Li Novel Polymyxin Combination With Antineoplastic Mitotane Improved the Bacterial Killing Against Polymyxin-Resistant Multidrug-Resistant Gram-Negative Pathogens Frontiers in Microbiology polymyxin mitotane repurposing combination therapy multidrug-resistance |
| title | Novel Polymyxin Combination With Antineoplastic Mitotane Improved the Bacterial Killing Against Polymyxin-Resistant Multidrug-Resistant Gram-Negative Pathogens |
| title_full | Novel Polymyxin Combination With Antineoplastic Mitotane Improved the Bacterial Killing Against Polymyxin-Resistant Multidrug-Resistant Gram-Negative Pathogens |
| title_fullStr | Novel Polymyxin Combination With Antineoplastic Mitotane Improved the Bacterial Killing Against Polymyxin-Resistant Multidrug-Resistant Gram-Negative Pathogens |
| title_full_unstemmed | Novel Polymyxin Combination With Antineoplastic Mitotane Improved the Bacterial Killing Against Polymyxin-Resistant Multidrug-Resistant Gram-Negative Pathogens |
| title_short | Novel Polymyxin Combination With Antineoplastic Mitotane Improved the Bacterial Killing Against Polymyxin-Resistant Multidrug-Resistant Gram-Negative Pathogens |
| title_sort | novel polymyxin combination with antineoplastic mitotane improved the bacterial killing against polymyxin resistant multidrug resistant gram negative pathogens |
| topic | polymyxin mitotane repurposing combination therapy multidrug-resistance |
| url | http://journal.frontiersin.org/article/10.3389/fmicb.2018.00721/full |
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