INHIBITION OF PLASMINOGEN ACTIVATION BY POLYMERIZED AMPICILLIN

The polymerized beta-lactam antibiotic ampicillin inhibits the proteol ytic activity of human plasmin upon I-125-labeled fibrin clots. The in hibition is dose-dependent, with half-maximal inhibition occurring at 1.25 mM of the polymerized antibiotic. Polymerized ampicillin also inh ibits binding of plasmin to fibrin, and 38% inhibition of binding occu rs at 10 mM of the antibiotic. Furthermore, polymerized ampicillin inh ibits the activation of plasminogen by either urokinase-like plasminog en activator (uPA) or tissue type-plasminogen activator (tPA). At 7.5 mM of polymerized ampicillin, the uPA-mediated plasminogen activation is suppressed by 94%, and half-maximal inhibition is obtained at 0.66 mM. The direct activity of uPA on the chromogenic substrate L-pyogluta myl-glycyl-L-arginine p-nitroanilide hydrochloride (S-2444) is unaffec ted by polymerized ampicillin levels of up to 10 mM. The inhibitory ef fects of the polymerized antibiotic on the activation of plasminogen b y both uPA and tPA is totally abolished in presence of fibrin. These i nteractions may serve as a novel model for ligands that enhance the cl ot-specificity of thrombolytic agents.