A NEW KETOLIDE, HMR-3004, ACTIVE AGAINST STREPTOCOCCI INDUCIBLY RESISTANT TO ERYTHROMYCIN

HMR 3004 is a new hydrazono ketolide characterized by a 3-keto functio n instead of the cladinose moiety. The effect of this antimicrobial ag ent on inducible and constitutive macrolide-lincosamide-streptogramin B (MLSB) resistance was tested in a lacZ reporter system under control of several ermAM-like attenuator variants. For one constitutively res istant Streptococcus agalactiae strain, three inducibly resistant Stre ptococcus pneumoniae strains, and one inducibly resistant Enterococcus faecalis strain, the attenuators fused with lacZ were cloned into the shuttle plasmid pJIM2246 and the plasmid,vas introduced into Staphylo coccus aureus RN4220. For the wild-type attenuators, HMR 3004 was a ve ry weak inducer, unlike its cladinose counterpart RU 6652 and erythrom ycin. As expected, for the fusion originating from the constitutively resistant S. agalactiae strain, the level of uninduced beta-galactosid ase synthesis was high. For one S. pneumoniae attenuator, mutations in the 3' end of the attenuator that weakened the stem-loop structure th at sequesters the ribosome-binding site and start codon for ermAM meth ylase could explain the high level of uninduced beta-galactosidase pro duced. For streptococci, the activity of HMR 3004 correlated with the basal level of beta-galactosidase synthesized, The weak inducer activi ty of HMR 3004 explained its activity against inducibly MLSB-resistant S. pneumoniae but did not correlate dth the moderate activity of the antibiotic against inducibly resistant E. faecalis.