A New Ketolide, HMR 3004, Active against Streptococci Inducibly Resistant to Erythromycin

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Abstract
HMR 3004 is a new hydrazono ketolide characterized by a 3-keto function instead of the cladinose moiety. The effect of this antimicrobial agent on inducible and constitutive macrolide-lincosamide-streptogramin B (MLS B ) resistance was tested in a lacZ reporter system under control of several ermAM -like attenuator variants. For one constitutively resistant Streptococcus agalactiae strain, three inducibly resistant Streptococcus pneumoniae strains, and one inducibly resistant Enterococcus faecalis strain, the attenuators fused with lacZ were cloned into the shuttle plasmid pJIM2246 and the plasmid was introduced into Staphylococcus aureus RN4220. For the wild-type attenuators, HMR 3004 was a very weak inducer, unlike its cladinose counterpart RU 6652 and erythromycin. As expected, for the fusion originating from the constitutively resistant S. agalactiae strain, the level of uninduced β-galactosidase synthesis was high. For one S. pneumoniae attenuator, mutations in the 3′ end of the attenuator that weakened the stem-loop structure that sequesters the ribosome-binding site and start codon for ermAM methylase could explain the high level of uninduced β-galactosidase produced. For streptococci, the activity of HMR 3004 correlated with the basal level of β-galactosidase synthesized. The weak inducer activity of HMR 3004 explained its activity against inducibly MLS B -resistant S. pneumoniae but did not correlate with the moderate activity of the antibiotic against inducibly resistant E. faecalis.