Bis-biguanide dihydrochloride inhibits intracellular replication of M. tuberculosis and controls infection in mice

Sci Rep. 2016 Sep 7:6:32725. doi: 10.1038/srep32725.

Abstract

While there is an urgent need to develop new and effective drugs for treatment of tuberculosis (TB) and multi-drug resistant TB (MDR-TB), repurposing FDA (U.S. Food and Drug Administration) -approved drugs for development of anti-TB agents may decrease time and effort from bench to bedside. Here, we employed host cell-based high throughput screening (HTS) assay to screen and characterize FDA-approved, off-patent library drugs for anti-Mycobacterium tuberculosis (MTB) activities. The cell-based HTS allowed us to identify an anti-cancer drug of bis-biguanide dihydrochloride (BBD) as potent anti-mycobacteria agent. Further characterization showed that BBD could inhibit intracellular and extracellular growth of M. smegmatis and slow-growing M. bovis BCG. BBD also potently inhibited replication of clinically-isolated MTB and MDR-TB strains. The proof-of-concept study showed that BBD treatment of MTB-infected mice could significantly decrease CFU counts in the lung and spleen. Notably, comparative evaluation showed that MTB CFU counts in BBD-treated mice were lower than those in rifampicin-treated mice. No apparent BBD side effects were found in BBD-treated mice. Thus, our findings support further studies to develop BBD as a new and effective drug against TB and MDR-TB.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antitubercular Agents / administration & dosage*
  • Antitubercular Agents / pharmacology
  • Biguanides / administration & dosage*
  • Biguanides / pharmacology
  • DNA Replication / drug effects
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Drug Repositioning
  • Humans
  • Lung / drug effects
  • Lung / microbiology
  • Mice
  • Mycobacterium bovis / drug effects
  • Mycobacterium smegmatis / drug effects
  • Mycobacterium tuberculosis / drug effects*
  • Spleen / drug effects
  • Spleen / microbiology
  • Tuberculosis, Multidrug-Resistant / drug therapy*
  • Tuberculosis, Multidrug-Resistant / microbiology

Substances

  • Antitubercular Agents
  • Biguanides