Multitarget Drug Discovery for Tuberculosis and Other Infectious Diseases

J Med Chem. 2014 Apr 10;57(7):3126-39. doi: 10.1021/jm500131s. Epub 2014 Apr 1.

Abstract

We report the discovery of a series of new drug leads that have potent activity against Mycobacterium tuberculosis as well as against other bacteria, fungi, and a malaria parasite. The compounds are analogues of the new tuberculosis (TB) drug SQ109 (1), which has been reported to act by inhibiting a transporter called MmpL3, involved in cell wall biosynthesis. We show that 1 and the new compounds also target enzymes involved in menaquinone biosynthesis and electron transport, inhibiting respiration and ATP biosynthesis, and are uncouplers, collapsing the pH gradient and membrane potential used to power transporters. The result of such multitarget inhibition is potent inhibition of TB cell growth, as well as very low rates of spontaneous drug resistance. Several targets are absent in humans but are present in other bacteria, as well as in malaria parasites, whose growth is also inhibited.

Publication types

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

MeSH terms

  • Anti-Infective Agents / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • Antitubercular Agents / pharmacology*
  • Bacteria / drug effects
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / pathology
  • Cell Proliferation / drug effects
  • Drug Design
  • Drug Discovery*
  • Female
  • Fungi / drug effects
  • Humans
  • MCF-7 Cells
  • Malaria, Falciparum / drug therapy
  • Malaria, Falciparum / parasitology
  • Membrane Transport Proteins / metabolism*
  • Models, Molecular
  • Molecular Structure
  • Mycobacterium tuberculosis / drug effects*
  • Plasmodium falciparum / drug effects
  • Structure-Activity Relationship
  • Tuberculosis / drug therapy
  • Tuberculosis / microbiology
  • Tumor Cells, Cultured

Substances

  • Anti-Infective Agents
  • Antineoplastic Agents
  • Antitubercular Agents
  • Membrane Transport Proteins