Dissociation of the antimicrobial activity of bacitracin USP from its renovascular effects

Abstract

Bacitracin is a nephrotoxic antibiotic that has recently been shown to induce contractile effects in aortas isolated from rabbits by stimulating receptors for 5-hydroxytryptamine (5-HT). The possible renovascular actions of this antibiotic were investigated. Bacitracin USP increased the vascular resistance in a concentration-dependent manner (9 to 175 micrograms/ml) in rat kidneys perfused with a constant flow of Krebs solution. This was significantly inhibited by 5-HT antagonists, but only partially at the higher bacitracin concentration. An antagonist of the chemotactic peptide fMet-Leu-Phe failed to influence the pressor effect of bacitracin in rat kidneys. Indomethacin modestly reduced the effect of all potent pressor agents in the rat organ. Bacitracin USP was separated in several fractions by using C18 reverse-phase chromatography. Two distinct fractions were vasoconstrictive when infused in rat kidneys; both fractions were 5-HT mimetics. These peaks were different from the major antibiotic peak, bacitracin A, which was identified by using analytical high-pressure liquid chromatography, mass spectrometry, and inhibition of Micrococcus luteus growth. The less polar vasoactive peak corresponded to at least two minor peptides of the bacitracin family. The most abundant of these vasoactive peptides had no direct contractile effect on an aorta isolated from a rabbit, but a preliminary metabolic study in rat kidneys suggests that it is apparently transformed into a potent 5-HT agonist that is active on the aorta preparation. Bacitracin A, the major constituent of bacitracin with antimicrobial activity, had no vasoconstrictor effect in the test systems that we used; however, we did rule out the possibility that the renovascular stimulants found in the bacitracin mixture do not derive spontaneously or by biotransformation from the antibacterial forms of bacitracin.