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Identification of small molecules that selectively inhibit streptokinase expression without suppression of viability in Group A streptococci - Probe 2

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

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 MLPCN library of over 300,000 compounds and identified a second small molecular probe. The probe ML134 (CID-1612038), 4-methoxy-2-(4-propoxyphenyl)quinazoline, selectively inhibits SK expression with an IC50 of 4.2 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 ML126 (CID-576989) and its analogs are another set of excellent molecular tools to investigate regulation of SK expression and mechanisms of GAS infection.