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Induction of ermSV by 16-membered-ring macrolide antibiotics
1Pharmacology Department, University of Wisconsin Medical School, Madison 53706, USA.
Abstract:
The erm family of 23S rRNA adenine-N6-methyltransferases confers resistance to all macrolide-lincosamide-streptograminB (MLS) antibiotics, but not all MLS antibiotics induce synthesis of Erm methyltransferase with equal efficiency in a given organism. The induction efficiency of a test panel of MLS antibiotics was studied by using two translational attenuator-lac reporter gene fusion constructs, one based on ermSV from Streptomyces viridochromogenes NRRL 2860 and the other based on ermC from Staphylococcus aureus RN2442. Four types of responses which were correlated with the macrolide ring size were seen, as follows: group 1, both ermSV and ermC were induced by the 14-membered-ring macrolides erythromycin, lankamycin, and matromycin, as well as by the lincosamide celesticetin; group 2, neither ermSV nor ermC was induced by the 12-membered-ring macrolide methymycin or by the lincosamide lincomycin or the streptogramin type B antibiotic ostreogrycin B; group 3, ermSV was selectively induced over ermC by the 16-membered-ring macrolides carbomycin, chalcomycin, cirramycin, kitasamycin, maridomycin, and tylosin; and group 4, ermC was selectively induced over ermSV by the 14-membered-ring macrolide megalomicin. These data suggest that the leader peptide determines the specificity of induction by different classes of MLS antibiotics and that for a given attenuator, a major factor which determines whether a given macrolide induces resistance is its size.
Insights
The erm gene confers resistance to macrolide-lincosamide-streptogramin B (MLS) antibiotics. Antibiotic-specific induction of erm gene expression depends on macrolide ring size and leader peptide sequences.
Area of Science:
- Microbiology
- Molecular Biology
- Antibiotic Resistance
Background:
- The erm gene family encodes 23S rRNA adenine-N6-methyltransferases, providing resistance to macrolide-lincosamide-streptogramin B (MLS) antibiotics.
- The efficiency of MLS antibiotic induction for Erm methyltransferase synthesis varies among different antibiotics and organisms.
Purpose of the Study:
- To investigate the induction efficiency of various MLS antibiotics on ermSV and ermC genes.
- To determine the correlation between macrolide ring size and the induction of erm gene expression.
Main Methods:
- Utilized two translational attenuator-lac reporter gene fusion constructs: one for ermSV and one for ermC.
- Tested the induction efficiency of a panel of MLS antibiotics, including macrolides, lincosamides, and streptogramin B.
Main Results:
- Observed four distinct response patterns correlated with macrolide ring size.
- 14-membered macrolides and celesticetin induced both ermSV and ermC.
- 16-membered macrolides selectively induced ermSV over ermC, while megalomicin selectively induced ermC over ermSV.
Conclusions:
- Leader peptide sequences are critical in determining the specificity of MLS antibiotic induction.
- Macrolide ring size is a major determinant of whether a macrolide induces resistance by modulating erm gene expression.