Antimicrobial properties and mode of action of the pyrrothine holomycin

Holomycin, a member of the pyrrothine class of antibiotics, displayed broad -spectrum antibacterial activity, inhibiting a variety of gram-positive and gram-negative bacteria, with the exception of Enterobacter cloacae. Morgan ella morganii, and Pseudomonas aeruginosa. The antibiotic lacked activity a gainst the eukaryotic microorganisms Saccharomyces cerevisiae and Candida k efyr. Holomycin exhibited a bacteriostatic response against Escherichia col i that was associated with rapid inhibition of RNA synthesis in whole cells . Inhibition of RNA synthesis could have been a secondary consequence of in hibiting tRNA aminoacylation, thereby inducing the stringent response. Howe ver, the levels of inhibition of RNA synthesis by holomycin were similar in a stringent and relaxed pair of E. coli strains that were isogenic except for the deletion of the relA gene. This suggests that inhibition of RNA syn thesis by holomycin could reflect direct inhibition of DNA-dependent RNA po lymerase, Examination of the effects of holomycin on the kinetics of the ap pearance of beta -galactosidase in induced E. coli cells was also consisten t with inhibition of RNA polymerase at the level of RNA chain elongation. H owever, holomycin only weakly inhibited E. coli RNA polymerase in assays us ing synthetic poly(dA-dT) and plasmid templates. Furthermore, inhibition of RNA polymerase was observed only at holomycin concentrations in excess of those required to inhibit the growth of E. coli. It is possible that holomy cin is a prodrug, requiring conversion in the cell to an active species tha t inhibits RNA polymerase.