Genetic basis of macrolide resistance in Mycobacterium avium isolated from patients with disseminated disease.

Important note: Information in this article was accurate in 1996. The state of the art may have changed since the publication date.

Genetic basis of macrolide resistance in Mycobacterium avium isolated from patients with disseminated disease.

Antimicrob Agents Chemother. 1995 Dec;39(12):2625-30. Unique Identifier : AIDSLINE GENBANK/X74494
Nash KA; Inderlied CB; Department of Pathology and Laboratory Medicine, Children's; Hospital Los Angeles, CA 90027, USA. kanash@hsc.usc.edu

Abstract: Clarithromycin (CLM) and azithromycin (AZM) are important agents in the treatment of disseminated Mycobacterium avium complex disease; however, monotherapy with these macrolides often leads to clinically significant resistance. The underlying resistance mechanism was investigated by comparing 23S rRNA gene sequences in the domain V region of 10 CLM-susceptible strains included in this study. The only differences in the domain V sequences associated with CLM resistance were at position 2274 of the complete M. avium 23S rRNA gene (GenBank accession no. X74494). All the CLM-susceptible strains had an A residue at this site, whereas seven of the eight CLM-resistant strains had either a C, G, or T. Four of these seven CLM-resistant strains emerged during monotherapy with CLM and two emerged during AZM monotherapy, showing that resistance selected by either macrolide was associated with mutation of the 23S rRNA gene. Thermodynamic analysis of secondary rRNA structure suggests that the observed mutations cause an alteration in free energy associated with rRNA folding, which may result in a localized conformation change in assembled ribosomes. Such a shift may be important in the resistance of ribosomes to the effects of macrolides. This study therefore establishes a link between mutations within the 23S rRNA gene and clinically significant macrolide resistance in M. avium and also identifies a possible molecular mechanism of resistance at the level of the ribosome.

Keywords: Antibiotics, Macrolide/*PHARMACOLOGY Azithromycin/PHARMACOLOGY AIDS-Related Opportunistic Infections/MICROBIOLOGY Base Sequence Clarithromycin/PHARMACOLOGY Drug Resistance, Microbial/GENETICS DNA, Bacterial/ANALYSIS/BIOSYNTHESIS/GENETICS Human Microbial Sensitivity Tests Molecular Sequence Data Mycobacterium avium Complex/*DRUG EFFECTS/*GENETICS Mycobacterium avium-intracellulare Infection/*MICROBIOLOGY Nucleic Acid Conformation Operon Polymerase Chain Reaction RNA, Bacterial/CHEMISTRY/GENETICS RNA, Messenger/BIOSYNTHESIS/GENETICS RNA, Ribosomal, 23S/CHEMISTRY/GENETICS Support, Non-U.S. Gov't Support, U.S. Gov't, P.H.S. JOURNAL ARTICLE

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M9660737

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