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From Breast Cancer to Antimicrobial: Combating Extremely Resistant Gram-Negative "Superbugs" Using Novel Combinations

Maytham H Hussein1, Elena K Schneider1, Alysha G Elliott2

  • 11 Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Australia .

Microbial Drug Resistance (Larchmont, N.Y.)
|December 10, 2016
PubMed

Insights

Novel therapies combining polymyxin B with selective estrogen receptor modulators (SERMs) show synergistic antibacterial activity against extremely drug-resistant Gram-negative pathogens. This combination offers a promising strategy for treating infections caused by these challenging "superbugs".

Area of Science:

  • Infectious Diseases
  • Microbiology
  • Pharmacology

Background:

  • Extremely drug-resistant (XDR) Gram-negative pathogens, or "superbugs," pose a significant threat, necessitating novel therapeutic strategies.
  • Polymyxin B is a last-resort antibiotic, but resistance is increasing, limiting its clinical utility.
  • Selective estrogen receptor modulators (SERMs) have not been extensively explored for their direct antibacterial properties or synergistic potential.

Purpose of the Study:

  • To investigate the synergistic antibacterial activity of polymyxin B in combination with SERMs against problematic Gram-negative pathogens.
  • To evaluate the efficacy of this combination against polymyxin-resistant isolates of Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii.

Main Methods:

  • In vitro assessment of synergistic activity using microdilution checkerboard and static time-kill assays.
  • Evaluation of bacterial killing, biofilm inhibition, membrane depolarization, and reactive oxygen species generation.
  • Microscopic analysis (scanning and transmission electron microscopy) to observe cellular damage.

Main Results:

  • Polymyxin B and SERMs (tamoxifen, raloxifene, toremifene) were ineffective as monotherapy against polymyxin-resistant Gram-negative bacteria.
  • Combination therapy demonstrated synergistic killing, reducing bacterial counts by ≥2-3 log10 CFU/ml after 24 hours.
  • Polymyxin B with toremifene showed potent activity against P. aeruginosa biofilms and induced significant membrane damage and cellular stress.

Conclusions:

  • The combination of polymyxin B and SERMs exhibits significant synergistic activity against XDR Gram-negative pathogens, including polymyxin-resistant strains.
  • This novel combination therapy strategy holds promise for treating infections caused by difficult-to-treat Gram-negative bacteria.
  • Further research into this combination could lead to new treatment options for nosocomial infections.
Keywords:
Gram-negativeSERMsmultidrug resistantpolymyxinrepositioning

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