Combinations of β-Lactam Antibiotics Currently in Clinical Trials Are Efficacious in a DHP-I-Deficient Mouse Model of Tuberculosis Infection

Antimicrob Agents Chemother. 2015 Aug;59(8):4997-9. doi: 10.1128/AAC.01063-15. Epub 2015 May 18.

Abstract

We report here a dehydropeptidase-deficient murine model of tuberculosis (TB) infection that is able to partially uncover the efficacy of marketed broad-spectrum β-lactam antibiotics alone and in combination. Reductions of up to 2 log CFU in the lungs of TB-infected mice after 8 days of treatment compared to untreated controls were obtained at blood drug concentrations and time above the MIC (T>MIC) below clinically achievable levels in humans. These findings provide evidence supporting the potential of β-lactams as safe and mycobactericidal components of new combination regimens against TB with or without resistance to currently used drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology*
  • Dipeptidases / deficiency*
  • Disease Models, Animal
  • Drug Therapy, Combination / methods
  • GPI-Linked Proteins / deficiency
  • Lung / metabolism
  • Lung / microbiology
  • Mice
  • Mice, Inbred C57BL
  • Microbial Sensitivity Tests / methods
  • Mycobacterium tuberculosis / drug effects
  • Respiratory Tract Infections / drug therapy*
  • Respiratory Tract Infections / metabolism
  • Respiratory Tract Infections / microbiology
  • Staphylococcal Infections / drug therapy
  • Staphylococcal Infections / metabolism
  • Staphylococcal Infections / microbiology
  • Tuberculosis / drug therapy*
  • Tuberculosis / metabolism
  • Tuberculosis / microbiology
  • beta-Lactams / pharmacology*

Substances

  • Anti-Bacterial Agents
  • GPI-Linked Proteins
  • beta-Lactams
  • Dipeptidases
  • dipeptidase 1