ABSTRACTMycobacterium abscessusinfections tend to respond poorly to macrolide-based chemotherapy, even though the organisms appear to be susceptible to clarithromycin. Circumstantial evidence suggested that at least someM. abscessusisolates might be inducibly resistant to macrolides. Thus, the purpose of this study was to investigate the macrolide phenotype ofM. abscessusclinical isolates. Inducible resistance to clarithromycin (MIC > 32 μg/ml) was found for 7 of 10 clinical isolates ofM. abscessuspreviously considered susceptible; the remaining 3 isolates were deemed to be susceptible (MIC ≤ 0.5 μg/ml). Inducible resistance was conferred by a novelermgene,erm(41), which was present in all 10 isolates and in an isolate ofMycobacterium bolletii(M. abscessustype II). However, theerm(41) alleles were nonfunctional in the three susceptibleM. abscessusisolates. No evidence oferm(41) was found inMycobacterium chelonae, and an isolate ofMycobacterium massilienseappeared to be anerm(41) deletion mutant. Expression oferm(41) inM. abscessusconferred resistance to clarithromycin and erythromycin and the ketolide HMR3004. However, this species was found to be intrinsically resistant, independent oferm(41), to clindamycin, quinupristin (streptogramin B), and telithromycin. The ability to confer resistance to clindamycin and telithromycin, but not quinupristin, was demonstrated by expressingerm(41) inMaycobacterium smegmatis. Exposure ofM. abscessusto the macrolide-lincosamide-streptogramin B-ketolide agents increased the levels oferm(41) mRNA 23- to 250-fold within 24 h. The inducible macrolide resistance phenotype of someM. abscessusisolates may explain the lack of efficacy of macrolide-based chemotherapy against this organism.

01 Jul 2006·Antimicrobial Agents and ChemotherapyQ2 · MEDICINE

Intrinsic Macrolide Resistance of the Mycobacterium tuberculosis Complex Is Inducible

Q2 · MEDICINE

Article

Author: Andini, Nadya ; Nash, Kevin A.

ABSTRACTMycobacterium tuberculosis is intrinsically resistant to macrolides, a characteristic associated with expression of the erm (37) gene. This intrinsic resistance was found to be inducible with clarithromycin and the ketolide HMR3004. Furthermore, underlying the phenotypic induction was an increase in erm (37) mRNA levels.

01 Oct 2004·Antimicrobial Agents and ChemotherapyQ2 · MEDICINE

Ketolide Antimicrobial Activity Persists after Disruption of Interactions with Domain II of 23S rRNA

Q2 · MEDICINE

Article

Author: Douthwaite, Stephen ; Novotny, Guy W. ; Andersen, Niels M. ; Jakobsen, Lene ; Poehlsgaard, Jacob

ABSTRACT Ketolides are the latest derivatives developed from the macrolide erythromycin to improve antimicrobial activity. All macrolides and ketolides bind to the 50S ribosomal subunit, where they come into contact with adenosine 2058 (A2058) within domain V of the 23S rRNA and block protein synthesis. An additional interaction at nucleotide A752 in the rRNA domain II is made via the synthetic carbamate-alkyl-aryl substituent in the ketolides HMR3647 (telithromycin) and HMR3004, and this interaction contributes to their improved activities. Only a few macrolides, including tylosin, come into contact with domain II of the rRNA and do so via interactions with nucleotides G748 and A752. We have disrupted these macrolide-ketolide interaction sites in the rRNA to assess their relative importance for binding. Base substitutions at A752 were shown to confer low levels of resistance to telithromycin but not to HMR3004, while deletion of A752 confers low levels of resistance to both ketolides. Mutations at position 748 confer no resistance. Substitution of guanine at A2058 gives rise to the MLS B (macrolide, lincosamide, and streptogramin B) phenotype, which confers resistance to all the drugs. However, resistance to ketolides was abolished when the mutation at position 2058 was combined with a mutation in domain II of the same rRNA. In contrast, the same dual mutations in rRNAs conferred enhanced resistance to tylosin. Our results show that the domain II interactions of telithromycin and HMR3004 differ from each other and from those of tylosin. The data provide no indication that mutations within domain II, either alone or in combination with an A2058 mutation, can confer significant levels of telithromycin resistance.

100 Deals associated with HMR-3004

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Indication	Highest Phase	Country/Location	Organization	Date
Bacterial Infections	Phase 1	-	Sanofi	-
Bacterial Infections	Phase 1	US	-	-
Toxoplasmosis	Phase 1	US	-	-
Respiratory Tract Infections	Preclinical	FR	Hoechst Marion Roussel, Inc.	17 Jul 1997

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