|Publication Type||Journal Article|
|Year of Publication||2012|
|Authors||An, WF, Metkar, SR, Nag, PP, Hartland, CL, Barker, D, Perez, JR, Sun, H, Macpherson, L, Palmer, M, Schreiber, SL|
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 the first small molecular probes. The probe ML126 (CID-576989), carbazol-9-yl-(4-methylphenyl)methanone, selectively inhibits SK expression with an IC50 of 3.6 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 excellent molecular tools to investigate regulation of SK expression and mechanisms of GAS infection.