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Novel Polymyxin Combination With Antineoplastic Mitotane Improved the Bacterial Killing Against Polymyxin-Resistant

Thien B Tran1,2, Jiping Wang1,2, Yohei Doi3

  • 1Monash Biomedicine Discovery Institute, Department of Microbiology, School of Biomedical Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia.

Frontiers in Microbiology
|May 1, 2018
PubMed

Insights

Combining polymyxin B with the cancer drug mitotane enhances killing of multidrug-resistant (MDR) Gram-negative bacteria. This combination therapy shows promise in preventing antibiotic resistance and offers a new strategy against challenging infections.

Area of Science:

  • Infectious Diseases
  • Antimicrobial Resistance
  • Pharmacology

Background:

  • Polymyxins are crucial for treating multidrug-resistant (MDR) Gram-negative bacterial infections due to limited new antibiotic development.
  • Polymyxin monotherapy leads to resistance; combination therapy improves efficacy and prevents resistance emergence.
  • Identifying novel antimicrobial agents is critical to combatting the rise of antibiotic resistance.

Purpose of the Study:

  • To evaluate the antineoplastic drug mitotane as a potential combination therapy with polymyxin B against polymyxin-resistant Gram-negative bacteria.
  • To investigate the synergistic antimicrobial activity and resistance-preventing potential of polymyxin B-mitotane combination therapy.

Main Methods:

  • Screened an FDA drug library to identify potential combination partners for polymyxin B.
  • Tested the combination of polymyxin B and mitotane against clinical isolates of carbapenem-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae.
  • Conducted time-kill studies, electron microscopy, and a mouse burn infection model to assess efficacy and mechanism.

Main Results:

  • The combination of polymyxin B and mitotane demonstrated enhanced in vitro antimicrobial activity against 10 MDR Gram-negative bacterial strains, including polymyxin-resistant isolates.
  • The combination provided superior bacterial killing within 6 hours and prevented resistance emergence in susceptible isolates.
  • Electron microscopy suggested the combination may interfere with bacterial cell division, and in vivo studies confirmed efficacy in a mouse model.

Conclusions:

  • Polymyxin B combined with mitotane exhibits significant synergistic antimicrobial activity against MDR Gram-negative bacteria.
  • This combination effectively enhances bacterial killing and prevents the emergence of polymyxin resistance.
  • Repurposing non-antibiotic drugs like mitotane offers a promising strategy to develop novel therapies against antibiotic-resistant infections.
Keywords:
combination therapymitotanemultidrug-resistancepolymyxinrepurposing

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