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Combating Multidrug-Resistant Pathogens with Host-Directed Nonantibiotic Therapeutics.

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Summary

Three repurposed drugs show significant protection against pneumonic plague, even when treatment is delayed. Amoxapine and doxapram efficacy increased with delayed treatment, offering up to 100% protection with levofloxacin.

Keywords:
Acinetobacter baumanniiClostridium difficileKlebsiella pneumoniaeYersinia pestisbubonic plaguein vitro assaysmouse modelsnew therapeuticspneumonic plague

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Area of Science:

  • Pharmacology
  • Infectious Diseases
  • Drug Discovery

Background:

  • Three FDA-approved drugs (trifluoperazine, amoxapine, doxapram) previously showed efficacy against pneumonic plague.
  • The study investigates the therapeutic potential of these drugs when administered later post-infection.

Purpose of the Study:

  • To evaluate the efficacy of trifluoperazine, amoxapine, and doxapram against pneumonic plague when administered up to 48 hours post-infection.
  • To assess the combination therapy of these drugs with levofloxacin or vancomycin against bacterial infections.
  • To identify non-antibiotic drugs effective against Klebsiella pneumoniae and Acinetobacter baumannii using a drug repurposing screen.

Main Methods:

  • Murine models were used to test drug efficacy against pneumonic plague, Clostridium difficile, Klebsiella pneumoniae, and Acinetobacter baumannii.
  • Drugs were administered at various time points, including up to 48 hours post-infection.
  • An in vitro macrophage cytotoxicity assay was employed to screen for novel drug candidates.

Main Results:

  • Amoxapine and doxapram efficacy improved with delayed administration (up to 24 hours) against pneumonic plague.
  • Combination therapy with levofloxacin provided up to 100% protection against plague at 48 hours post-infection.
  • All three drugs combined with vancomycin offered 80-100% protection against Clostridium difficile infection at 24 hours post-infection.
  • Amoxapine demonstrated 40-60% protection against Klebsiella pneumoniae.
  • Drug repurposing identified 76/780 drugs effective against K. pneumoniae and 121 against Acinetobacter baumannii, with six showing broad activity.

Conclusions:

  • Repurposed non-antibiotic drugs show significant therapeutic potential against serious bacterial infections, including multidrug-resistant pathogens.
  • Delayed administration of amoxapine and doxapram enhances their efficacy against pneumonic plague.
  • Drug repurposing screening is a viable strategy for identifying novel therapeutics against public health-concerning pathogens.