Evaluation of tirandamycins with selective activity against Enterococci in the silkworm infection model

In the course of screening for anti-enterococcal antibiotics from microbial resources, a new tirandamycin congener (1), together with four known tirandamycins (2 to 5), were isolated from Streptomyces tirandamycinicus TMPU-20A040. The structures of these tirandamycins were elucidated using NMR and MS analyses; 1 was identified as 12-carboxy tirandamycin A and 2 to 5 as known tirandamycins A (2), B (3), E (4), and J (5). Compounds 1 to 3 exhibited selective anti-Enterococci activity, including vancomycin-resistant strains, with MIC in the range of 1.0 to 64 µg ml^-1 in the microdilution method. 2 and 3 exerted weak therapeutic effects in the in vivo-mimic silkworm Enterococcus faecalis infection model with ED₅₀ values of 150 and 75 µg larva^-1 g^-1, respectively, indicating that the in vivo activities of 2 and 3 were lower than their in vitro activities. Further investigations into the causes of the decreased in vivo activities of 2 and 3 suggested the low plasma protein binding ratio of these compounds, but revealed short half-lives of 6.3 and 16 min, respectively, in the silkworm hemolymph.