Selective killing of nonreplicating mycobacteria. Academic Article uri icon

Overview

MeSH

  • Animals
  • Cells, Cultured
  • Colony Count, Microbial
  • Enzyme Inhibitors
  • Gene Deletion
  • Genetic Complementation Test
  • Guinea Pigs
  • Hypoxia
  • Lung
  • Macrophages
  • Molecular Structure
  • Nitric Oxide
  • Tuberculosis
  • Virulence
  • Virulence Factors

MeSH Major

  • Acyltransferases
  • Antitubercular Agents
  • Bacterial Proteins
  • Microbial Viability
  • Mycobacterium tuberculosis
  • Rhodanine

abstract

  • Antibiotics are typically more effective against replicating rather than nonreplicating bacteria. However, a major need in global health is to eradicate persistent or nonreplicating subpopulations of bacteria such as Mycobacterium tuberculosis (Mtb). Hence, identifying chemical inhibitors that selectively kill bacteria that are not replicating is of practical importance. To address this, we screened for inhibitors of dihydrolipoamide acyltransferase (DlaT), an enzyme required by Mtb to cause tuberculosis in guinea pigs and used by the bacterium to resist nitric oxide-derived reactive nitrogen intermediates, a stress encountered in the host. Chemical screening for inhibitors of Mtb DlaT identified select rhodanines as compounds that almost exclusively kill nonreplicating mycobacteria in synergy with products of host immunity, such as nitric oxide and hypoxia, and are effective on bacteria within macrophages, a cellular reservoir for latent Mtb. Compounds that kill nonreplicating pathogens in cooperation with host immunity could complement the conventional chemotherapy of infectious disease.

publication date

  • March 13, 2008

has subject area

  • Acyltransferases
  • Animals
  • Antitubercular Agents
  • Bacterial Proteins
  • Cells, Cultured
  • Colony Count, Microbial
  • Enzyme Inhibitors
  • Gene Deletion
  • Genetic Complementation Test
  • Guinea Pigs
  • Hypoxia
  • Lung
  • Macrophages
  • Microbial Viability
  • Molecular Structure
  • Mycobacterium tuberculosis
  • Nitric Oxide
  • Rhodanine
  • Tuberculosis
  • Virulence
  • Virulence Factors

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC2423947

Digital Object Identifier (DOI)

  • 10.1016/j.chom.2008.02.003

PubMed ID

  • 18329613

Additional Document Info

start page

  • 137

end page

  • 145

volume

  • 3

number

  • 3