BE-18591 as a new H(+)/Cl(-) symport ionophore that inhibits immunoproliferation and gastritis.

In our previous papers [e.g. Sato et al., J. Biol. Chem. 273 (1998) 21455-21462], we have shown that prodigiosins can uncouple various H(+)-ATPases through their H(+)/Cl(-) symport activity. BE-18591 is an enamine of 4-methoxy-2,2'-bipyrrole-5-carboxyaldehyde (tambjamine group antibiotics) which resembles the prodigiosins. We found that BE-18591 was a new group of antibiotics that uncouples various H(+)-ATPases: it inhibited proton pump activities with IC(50)s of about 1-2 nM (about 20 pmol/mg protein) for submitochondrial particles as well as gastric vesicles and of 230 nM (about 230 pmol/mg protein) for lysosomes, but it had little effect on their ATP hydrolyses (up to 10 microM), a property of H(+)/Cl(-) symport activity. At low concentrations (<1 microM), BE-18591 inhibited immunoproliferation, the IC(50) of lipopolysaccharide-stimulated mouse splenocytes was 38 nM, that of Concanavalin A-stimulated cells was 230 nM. Gastritis of rabbits was also inhibited. At higher concentrations (>1 microM), BE-18591 induced neurite outgrowth (15% induction in 48 h at 4 microM), inhibited bone resorption (approximately 35% in 48 h at 10 microM) and caused cell death (approximately 30% in 48 h at 4 microM) but with little apoptosis.