Foundations of antibiotic resistance in bacterial physiology: the mycobacterial paradigm

Trends Microbiol. 2006 Jul;14(7):304-12. doi: 10.1016/j.tim.2006.05.005. Epub 2006 Jun 8.

Abstract

The intrinsic resistance of Mycobacterium tuberculosis and related pathogens to most common antibiotics limits chemotherapeutic options to treat tuberculosis and other mycobacterial diseases. Resistance has traditionally been attributed to the unusual multi-layer cell envelope that functions as an effective barrier to the penetration of antibiotics. Recent insights into mechanisms that neutralize the toxicity of antibiotics in the cytoplasm have revealed systems that function in synergy with the permeability barrier to provide intrinsic resistance. Here, we highlight the growing pool of information about internal, antibiotic-responsive regulatory proteins and corresponding resistance genes, and present new concepts that rationalize how they might have evolved. Pharmaceutical inhibition of these intrinsic systems could make many previously available antibiotics active against M. tuberculosis.

MeSH terms

  • Anti-Bacterial Agents / metabolism
  • Anti-Bacterial Agents / pharmacology
  • Bacterial Proteins / genetics
  • Bacterial Proteins / physiology
  • Cell Wall / physiology
  • Cell Wall / ultrastructure
  • Cysteine
  • Disaccharides / metabolism
  • Disaccharides / physiology
  • Drug Resistance, Multiple, Bacterial / genetics
  • Drug Resistance, Multiple, Bacterial / physiology*
  • Glycopeptides
  • Inositol
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / physiology
  • Models, Biological
  • Mycobacterium / drug effects
  • Mycobacterium / genetics
  • Mycobacterium / physiology
  • Mycobacterium tuberculosis / drug effects
  • Mycobacterium tuberculosis / genetics
  • Mycobacterium tuberculosis / metabolism*
  • Permeability
  • Porins / genetics
  • Porins / physiology
  • Pyrazoles / metabolism
  • Sulfhydryl Compounds / metabolism
  • Sulfhydryl Compounds / physiology
  • Transcription Factors / genetics
  • Transcription Factors / physiology

Substances

  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Disaccharides
  • Glycopeptides
  • Membrane Transport Proteins
  • Porins
  • Pyrazoles
  • Sulfhydryl Compounds
  • Transcription Factors
  • mycothiol
  • Inositol
  • Cysteine