Himastatin, a cyclohexadepsipeptide
antibiotic, had in vivo antitumor activity against localized
P388 leukemia and
B16 melanoma but had no distal site antitumor activity. An in vitro Bacillus subtilis well-
agar diffusion assay was employed to test the hypothesis that
himastatin was enzymatically inactivated. The activity of
himastatin against B. subtilis was inhibited when
himastatin was mixed with mouse liver S9 fraction and microsomes. However, subsequent investigations demonstrated that the markedly decreased antibacterial activity was not enzymatic in 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 more reduced the antimicrobial activity of
himastatin 50 to 100 times. If
antibiotics such as
ampicillin,
bacitracin,
chloramphenicol, and
tunicamycin 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
himastatin. Importantly, the activity of
himastatin against HCT-116
colon adenocarcinoma cells in soft
agar was markedly reduced in the presence of
sodium palmitate as the reference
fatty acid salt. The data indicate that
himastatin may be trapped in
micelles in vitro. It may be speculated 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 effects of
himastatin may result from interactions with the cell membrane.