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A greater effect on clarithromycin resistance of mef(A)-associated msr(D) than mef(E)-associated msr(D) in
Ichiro Tatsuno1, Masanori Isaka1, Tadao Hasegawa1
1Department of Bacteriology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Abstract:
The mef(A)- and its subclass mef(E) systems had long been considered to constitute one of the primary macrolide-resistant mechanisms in Streptococcus pyogenes. However, we have previously demonstrated that the msr(D) gene located immediately downstream of the mef(A)/mef(E) genes plays a predominant role in these systems. In previous studies, furthermore, mef(A)-associated msr(D)10-85 of an S. pyogenes strain (10-85) exhibited a greater increase in clarithromycin minimum inhibitory concentration (MIC) than mef(E)-associated msr(D)13-O-10 of another strain (13-O-10). Both msr(D) genes encode 487 amino acid residues, 13 amino acid residues of which are different from each other. In this study, we performed mutational analysis of the msr(D) genes and showed that a single-nucleotide polymorphism to cause a substitution of Asp238 with Gly is mainly associated with the greater increase in clarithromycin MIC by the msr(D)10-85 than by the msr(D)13-O-10 allele. In addition, another substitution of Ser with Arg at codon 194 is partially associated with the greater increase by the msr(D)10-85 than by the msr(D)13-O-10 allele.
Insights
The msr(D) gene, not mef(A)/mef(E), is key for macrolide resistance in Streptococcus pyogenes. Specific msr(D) gene variations, like Asp238Gly, significantly increase resistance to clarithromycin.
Area of Science:
- Microbiology
- Molecular Biology
- Genetics
Background:
- Macrolide resistance in Streptococcus pyogenes is primarily attributed to mef(A)/mef(E) systems.
- Previous research identified the msr(D) gene, located downstream of mef(A)/mef(E), as a predominant factor in macrolide resistance.
- Distinct msr(D) alleles (msr(D)10-85 and msr(D)13-O-10) show differential impacts on clarithromycin minimum inhibitory concentration (MIC).
Purpose of the Study:
- To investigate the specific genetic variations within the msr(D) gene responsible for differential macrolide resistance.
- To elucidate the molecular mechanisms underlying the increased clarithromycin MIC associated with specific msr(D) alleles in Streptococcus pyogenes.
Main Methods:
- Mutational analysis of msr(D) genes from Streptococcus pyogenes strains.
- Comparative analysis of clarithromycin MIC values for strains with different msr(D) alleles.
- Identification of single-nucleotide polymorphisms (SNPs) and their corresponding amino acid substitutions.
Main Results:
- A single-nucleotide polymorphism causing an Asp238Gly substitution in msr(D)10-85 is primarily responsible for its higher clarithromycin MIC compared to msr(D)13-O-10.
- An additional substitution (Ser194Arg) in msr(D)10-85 partially contributes to the elevated clarithromycin MIC.
- Both msr(D) alleles encode proteins of 487 amino acids, with 13 differing residues between the two variants.
Conclusions:
- The msr(D) gene, rather than mef(A)/mef(E), plays a crucial role in macrolide resistance in Streptococcus pyogenes.
- Specific amino acid substitutions within the msr(D) gene, particularly Asp238Gly, significantly influence the level of resistance to clarithromycin.
- Understanding these genetic determinants is vital for developing effective strategies against macrolide-resistant Streptococcus pyogenes infections.
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