Novel polymyxin combination with antineoplastic mitotane improved the bacterial killing against polymyxin-resistant multidrug-resistant gram-negative pathogens

Thien B. Tran, Jiping Wang, Yohei Doi, Tony Velkov, Phillip J. Bergen, Jian Li

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number721
JournalFrontiers in Microbiology
Volume9
Issue numberAPR
DOIs
Publication statusPublished - 12-04-2018

Fingerprint

Mitotane
Polymyxins
Antineoplastic Agents
Polymyxin B
Acinetobacter baumannii
Gram-Negative Bacteria
Klebsiella pneumoniae
Pseudomonas aeruginosa
Preclinical Drug Evaluations
Carbapenems
Microbial Drug Resistance
Cell Division
Libraries
Electron Microscopy
Therapeutics
Anti-Bacterial Agents

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Microbiology (medical)

Cite this

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title = "Novel polymyxin combination with antineoplastic mitotane improved the bacterial killing against polymyxin-resistant multidrug-resistant gram-negative pathogens",
abstract = "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.",
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Novel polymyxin combination with antineoplastic mitotane improved the bacterial killing against polymyxin-resistant multidrug-resistant gram-negative pathogens. / Tran, Thien B.; Wang, Jiping; Doi, Yohei; Velkov, Tony; Bergen, Phillip J.; Li, Jian.

In: Frontiers in Microbiology, Vol. 9, No. APR, 721, 12.04.2018.

Research output: Contribution to journalArticle

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AU - Tran, Thien B.

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AB - 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.

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