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.