INHIBITION OF ANTIBACTERIAL ACTIVITY OF HIMASTATIN, A NEW ANTITUMOR ANTIBIOTIC FROM STREPTOMYCES-HYGROSCOPICUS, BY FATTY-ACID SODIUM-SALTS

Himastatin, a cyclohexadepsipeptide antibiotic, had in vivo antitumor activity against localized P388 leukemia and B16 melanoma but had no d istal site antitumor activity. An in vitro Bacillus subtilis well-agar diffusion assay was employed to test the hypothesis that himastatin w as enzymatically inactivated. The activity of himastatin;against B. su btilis was inhibited when himastatin was mixed with mouse liver So fra ction and microsomes. However, subsequent investigations demonstrated that the markedly decreased antibacterial activity was not enzymatic i n nature but was related to the presence of certain fatty acid salts. Saturated fatty acid sodium salts with a carbon chain number of 8 or m ore reduced the antimicrobial activity of himastatin 50 to 100 times. If antibiotics such as ampicillin, bacitracin, chloramphenicol, and tu nicamycin were used in place of himastatin, no meaningful reduction in antibacterial activity occurred. However, the antibacterial activity of the membrane-active peptide antibiotic polymyxin B, but not that of polymyxin E (colistin), was reduced in a manner similar to that of hi mastatin. Importantly, the activity of himastatin against HCT-116 colo n adenocarcinoma cells in soft agar was markedly reduced in the presen ce of sodium palmitate as the reference fatty acid salt. The data indi cate that himastatin may be trapped in micelles in vitro. It may be sp eculated that the lack of distal site antitumor activity resulted from similar complex formation between himastatin and lipids in vivo. The results also suggest that the cancer cytotoxic and antimicrobial effec ts of himastatin may result from interactions with the cell membrane.