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

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.

SUBMITTER: Nash KA

PROVIDER: S-EPMC163001 | biostudies-literature | 1995 Dec

REPOSITORIES: biostudies-literature

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

Nash K A KA Inderlied C B CB

Antimicrobial agents and chemotherapy 19951201 12

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 th ...[more]

PMID: 8592991

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Project description:Mycobacterium avium subsp. hominissuis mainly causes disseminated infection in immunocompromised hosts, such as individuals with human immunodeficiency virus (HIV) infection, and pulmonary infection in immunocompetent hosts. However, many aspects of the different types of M. avium subsp. hominissuis infection remain unclear. We examined the antibiotic susceptibilities and genotypes of M. avium subsp. hominissuis isolates from different hosts by performing drug susceptibility testing using eight antibiotics (clarithromycin, rifampin, ethambutol, streptomycin, kanamycin, amikacin, ethionamide, and levofloxacin) and variable-number tandem-repeat (VNTR) typing analysis for 46 isolates from the sputa of HIV-negative patients with pulmonary M. avium subsp. hominissuis disease without previous antibiotic treatment and 30 isolates from the blood of HIV-positive patients with disseminated M. avium subsp. hominissuis disease. Interestingly, isolates from pulmonary M. avium subsp. hominissuis disease patients were more resistant to seven of the eight drugs, with the exception being rifampin, than isolates from HIV-positive patients. Moreover, VNTR typing analysis showed that the strains examined in this study were roughly classified into three clusters, and the genetic distance from reference strain 104 for isolates from pulmonary M. avium subsp. hominissuis disease patients was statistically significantly different from that for isolates from HIV-positive patients (P = 0.0018), suggesting that M. avium subsp. hominissuis strains that cause pulmonary and disseminated disease have genetically distinct features. Significant differences in susceptibility to seven of the eight drugs, with the exception being ethambutol, were noted among the three clusters. Collectively, these results suggest that an association between the type of M. avium subsp. hominissuis infection, drug susceptibility, and the VNTR genotype and the properties of M. avium subsp. hominissuis strains associated with the development of pulmonary disease are involved in higher levels of antibiotic resistance.

Dataset Information

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

Publications

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

Similar Datasets

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