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DOI:

Identification of small molecules that selectively inhibit streptokinase expression without suppression of viability in Group A streptococci - Probe 3

Publication TypeJournal Article
Year of Publication2012
AuthorsAn, WF, Metkar, SR, Youngsaye, W, Nag, PP, Hartland, CL, Barker, D, Perez, JR, Sun, H, Macpherson, L, Palmer, M, Schreiber, SL
Date Published2012/01/09
Abstract

Streptokinase is a major group A streptococcus (GAS) virulence factor and plays
critical roles in GAS pathogenicity. We set out to identify and develop novel small
molecule probes that inhibit streptokinase (SK) expression in GAS without
suppressing cell growth to minimize potential drug resistance. We screened the Molecular Libraries Probe Centers Network (MLPCN)
library of over 300,000 compounds and identified a third small molecular probe. The
probe (CID-2769229/ML135),
2-chloro-N-(3-cyano-4-((4-methoxyphenyl)thio)phenyl)benzamide,
selectively inhibits SK expression with an IC50 of 1.9 μM in a
GAS strain and has no effect on bacterial growth. A series of analogs were
synthesized to explore the structure activity relationships. These analogs showed
over 10-fold range in potency of inhibition of SK expression, and revealed key
structural requirements for optimal potency and selectivity. The probe
(CID-576989/ML135) and its analogs are another set
of excellent molecular tools to investigate regulation of SK expression and
mechanisms of GAS infection.

Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/21735609?dopt=Abstract