The antibacterial activity of the nitrogen heterocyclic sponge constituent cribrostatin 6 was examined. Cribrostatin 6 was bacteriostatic for a variety of Gram-positive species and was bactericidal for the majority of clinical isolates of Streptococcus pneumoniae, including penicillin-resistant strains. Minimum bactericidal concentration/MIC ratios were < or =2 for 75 % of S. pneumoniae clinical isolates. Kill-curve analysis confirmed the bactericidal action of cribrostatin 6. Bactericidal activity was rather slow, beginning at 2, 4 or 8 h, depending on the strain. The frequency of occurrence of bacterial spontaneous mutations to resistance was < or =10(-7). The maximum tolerated dose of cribrostatin 6 in mice was 750-1000 micro g kg(-1) day(-1). Cribrostatin 6 is a promising lead antibiotic for Gram-positive bacteria, particularly S. pneumoniae, a leading cause of infection and mortality worldwide.
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