GRAMICIDIN-S IS ACTIVE AGAINST BOTH GRAM-POSITIVE AND GRAM-NEGATIVE BACTERIA

Four linear and four cyclic analogs of gramicidin S (GS) in which D-Ph e was replaced with either D-His, D-Ser, D-Tyr or D-Asn have been prep ared by solid-phase peptide synthesis and characterized with respect t o antibacterial, antifungal and hemolytic activity. Unlike previous re ports, GS and a number of cyclic analogs were found to be active again st gram-positive as well as gram-negative bacteria. GS showed MICs ran ging from 3 to 12.5 mu g/mL for gram-negative bacteria, compared to MI Cs of 3 mu g/mL for gram-positive bacteria. Furthermore, these analogs were also found to exhibit antifungal activity. Unlike the cyclic ana logs, all linear analogs were found to be inactive against a wide rang e of microorganisms tested, and showed low levels of hemolytic activit y, The antibacterial activity was found to be highly dependent on the type of assay used, with solution-based assays showing greater activit y against gramnegative bacteria than agar-based assays. The GS cyclic analogs were all less toxic than GS itself, with the analog containing the D-Phe to D-Tyr substitution showing the greatest activity of the synthetic analogs. Hemolytic activity in solution against human and sh eep red blood cells paralleled antibiotic activity, with those peptide s exhibiting greater antibiotic activity generally showing greater hem olytic activity. Membrane destabilization as monitored using the hydro phobic probe N-phenyl-1-naphthylamine was also found to parallel antib acterial and hemolytic activity of cyclic and linear analogs. These re sults indicate that GS and certain related analogs may have applicatio ns as broad-spectrum antibiotics and should be reevaluated for such pu rposes. (C) Munksgaard 1996.