Selective Killing of Nonreplicating Mycobacteria

Ruslana Bryk, Benjamin Gold, Aditya Venugopal, Jasbir Singh, Raghu Samy, Krzysztof Pupek, Hua Cao, Carmen Popescu, Mark Gurney, Srinivas Hotha, Joseph Cherian, Kyu Rhee, Lan Ly, Paul J. Converse, Sabine Ehrt, Omar Vandal, Xiuju Jiang, Jean Schneider, Gang Lin, Carl Nathan

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)137-145
Number of pages9
JournalCell Host and Microbe
Volume3
Issue number3
DOIs
StatePublished - Mar 13 2008

Keywords

  • CHEMBIO
  • HUMDISEASE
  • MICROBIO

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology

Fingerprint Dive into the research topics of 'Selective Killing of Nonreplicating Mycobacteria'. Together they form a unique fingerprint.

Cite this