Inhibition of antibacterial activity of himastatin, a new antitumor antibiotic from Streptomyces hygroscopicus, by fatty acid sodium salts

Abstract

Himastatin, a cyclohexadepsipeptide antibiotic, had in vivo antitumor activity against localized P388 leukemia and B16 melanoma but had no distal site antitumor activity. An Himastatin is a dimeric cyclohexadepsipeptide antibiotic isolated from fermentation broths of Streptomyces hygroscopicus (9, 10). The proposed structure of himastatin is shown in Fig. 1. The compound had antimicrobial activity against grampositive bacteria and was cytotoxic to mammalian tumor cell lines in vitro. Himastatin also was active against both murine P388 leukemia and B16 melanoma (intraperitoneal-intraperitoneal [i.p.-i.p.] models) (9). However, activity was not obtained against intravenously implanted P388. It was hypothesized that the lack of distal site antitumor activity in vivo resulted from either poor bioavailability or metabolic inactivation. A soluble formulation of himastatin was developed; this preparation was active against P388 in the i.p.-i.p. model but also was inactive in the intravenous-intravenous P388 model. The metabolic inactivation hypothesis then was evaluated with an in vitro model on the basis of activity against Bacillus subtilis. It was found that mouse liver homogenates markedly inhibited the activity of himastatin against B. subtilis. However, it was demonstrated further that the inhibitory effects were not metabolic or enzymatic in nature. Thus, the purpose of this research was to investigate the nature of the inhibition of B. subtilis activity by himastatin in the presence of liver homogenates.

Total synthesis of himastatin

“…Separately, the similarity in MIC values and cellular morphology among our series of synthetic himastatin stereoisomers reveals that achiral interactions—for example, with the hydrophobic groups of phospholipids ( 34 , 35 )—are largely responsible for the observed antibiotic activity. In summary, our chemical biology studies using our synthetic probes offer findings that are consistent with the hypothesis that (–)-himastatin’s ( 1 ) antibiotic activity is dependent on interaction with bacterial membranes ( 7 ). It is evident that (–)-himastatin ( 1 ) is a distinct member among known membrane disruptors ( 41 ).…”

Total Synthesis of Himastatin

“…Separately, the similarity in MIC values and cellular morphology amongst our series of synthetic himastatin stereoisomers reveals that achiral interactions, for example with the hydrophobic groups of phospholipids (34,35), are largely responsible for the observed antibiotic activity. In summary, our chemical biology studies using our synthetic probes offer findings that are consistent with the hypothesis that (-)-himastatin's (1) antibiotic activity is dependent on interaction with bacterial membranes (7). It is evident that (-)-himastatin (1) is a structurally unique member amongst known membrane-disruptors.…”

Design and Biosynthesis of Dimeric Alboflavusins with Biaryl Linkages via Regiospecific C–C Bond Coupling

“…Compound 3 was observed to lack distal site antitumor activity in vivo. The decrease of bioactivities of 3 in vivo was found to be related to certain fatty acid sodium salts, and it was shown that 3 could be trapped in the micelles formed by the fatty acid salts, which indicated that 3 might execute its inhibition effects by interacting with cell membrane . Compound 1 was also proposed to execute its inhibition effects by damaging cell membrane according to the scanning electron microscope data of cells treated with 1 .…”