Inhibitor of streptokinase gene expression improves survival after group A streptococcus infection in mice

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.

A Bacterial Pathogen Co-opts Host Plasmin to Resist Killing by Cathelicidin Antimicrobial Peptides

“…Blocking the ability of GAS to acquire Ska-activated plasmin activity on its surface, either by genetic manipulation of Ska or by inhibition of plasmin activity with aprotinin, significantly reduced virulence in a murine infection model. Pharmacological inhibition of Ska in combination with other virulence determinants has recently been shown to reduce GAS virulence in mice (28). Our data have shown that inhibition of plasmin protease activity (the critical effector mechanism of Ska) is sufficient to reduce GAS virulence in a murine skin infection model.…”

Chemical Biology Applied to the Study of Bacterial Pathogens

“…Using this well-established model (59), mice were subcutaneously injected with GAS, given a day to establish an infection, and then intraperitoneally treated with compound daily for 5 days. Mice treated with CCG-2979 showed a statistically significant improvement in survival, while those treated with the CCG-102487 analog were not protected from GAS-induced mortality (7).…”

“…The effect of one chemical analog, CCG-102487, on global gene expression was examined by microarray analysis, which demonstrated that expression of 29% of GAS genes in addition to that of ska was altered, with the vast majority of them being reduced in expression. Included among these were other virulence-associated genes coding for adhesins and toxins, along with genes encoding some metabolic functions (7).…”

2013 Lucian Award

“…After screening more than 300 000 chemicals, Ginsburg and colleagues 5 identified a small set that specifically turned off streptokinase in the bacteria, several of which proved effective in protecting group A streptococci-sensitive mice from fatal infection.…”