Inhibitor of Streptokinase Gene Expression Improves Survival After Group A Streptococcus Infection in Mice

Proc Natl Acad Sci U S A. 2012 Feb 28;109(9):3469-74. doi: 10.1073/pnas.1201031109. Epub 2012 Feb 13.

Abstract

The widespread occurrence of antibiotic resistance among human pathogens is a major public health problem. Conventional antibiotics typically target bacterial killing or growth inhibition, resulting in strong selection for the development of antibiotic resistance. Alternative therapeutic approaches targeting microbial pathogenicity without inhibiting growth might minimize selection for resistant organisms. Compounds inhibiting gene expression of streptokinase (SK), a critical group A streptococcal (GAS) virulence factor, were identified through a high-throughput, growth-based screen on a library of 55,000 small molecules. The lead compound [Center for Chemical Genomics 2979 (CCG-2979)] and an analog (CCG-102487) were confirmed to also inhibit the production of active SK protein. Microarray analysis of GAS grown in the presence of CCG-102487 showed down-regulation of a number of important virulence factors in addition to SK, suggesting disruption of a general virulence gene regulatory network. CCG-2979 and CCG-102487 both enhanced granulocyte phagocytosis and killing of GAS in an in vitro assay, and CCG-2979 also protected mice from GAS-induced mortality in vivo. These data suggest that the class of compounds represented by CCG-2979 may be of therapeutic value for the treatment of GAS and potentially other gram-positive infections in humans.

Publication types

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

MeSH terms

  • Animals
  • Anti-Bacterial Agents / isolation & purification
  • Anti-Bacterial Agents / pharmacology
  • Anti-Bacterial Agents / therapeutic use*
  • Depression, Chemical
  • Drug Evaluation, Preclinical
  • Enzyme Induction / drug effects
  • Gene Expression Regulation, Bacterial / drug effects*
  • High-Throughput Screening Assays
  • Host Specificity / genetics
  • Humans
  • Kanamycin Resistance / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Molecular Structure
  • Phagocytosis / drug effects
  • Plasminogen / genetics
  • Promoter Regions, Genetic / genetics
  • Quinazolines / isolation & purification
  • Quinazolines / pharmacology
  • Quinazolines / therapeutic use*
  • Small Molecule Libraries
  • Streptococcal Infections / drug therapy*
  • Streptococcus pyogenes / drug effects*
  • Streptococcus pyogenes / enzymology
  • Streptococcus pyogenes / genetics
  • Streptococcus pyogenes / pathogenicity
  • Streptokinase / antagonists & inhibitors*
  • Streptokinase / biosynthesis
  • Streptokinase / genetics
  • Virulence / drug effects
  • Virulence / genetics

Substances

  • Anti-Bacterial Agents
  • CCG-2979
  • Quinazolines
  • Small Molecule Libraries
  • Plasminogen
  • Streptokinase