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Neplanocin A, a cyclopentenyl analog of adenosine, is a naturally occurring antibiotic possessing potent inhibitory activity toward the enzyme S-adenosylhomocysteine (AdoHcy) hydrolase. In the present study, we examined whether there was a correlation between the inhibition of prokaryotic AdoHcy hydrolase and the reported antibacterial activity of neplanocin A, e.g. Alcaligenes faecalis (Yaginuma et al., J. Antibiotics 34: 359 approximately 366, 1981). Of 16 bacterial species screened, only 2 organisms (both of which contained AdoHcy hydrolase) were sensitive to 10 nM neplanocin A when grown on agar plates. None of the 16 strains showed any growth sensitivity in broth culture to concentrations of the antibiotic as high as 4 mM. However, treatment of A. faecalis in broth culture with 14 microM neplanocin A resulted in complete inhibition of cellular AdoHcy hydrolase and subsequent elevation of intracellular AdoHcy. No alternative method for degrading or removing the excess AdoHcy from these cells was detected. Bacillus subtilis, which exhibited no AdoHcy hydrolase activity showed no alteration of AdoHcy metabolism when treated with the same concentration of the antibiotic. These results indicate that inhibition of AdoHcy hydrolase is not related to the antibacterial activity of neplanocin A and suggest that using this enzyme as a target for the design of antimicrobial agents is not likely to prove a productive approach.