title: Predominant role of msr(D) over mef(A) in macrolide resistance in Streptococcus pyogenes.
abstract: In Japan, the number of patients with streptococcal toxic shock syndrome is reported to be increasing. mef(A) gene-positive macrolide-resistant emm1 strains are thought to possibly contribute to the rise in the frequency of STSS. Although analyses of macrolide-resistant mechanisms, including mef(A) resistance, have been performed mainly in Streptococcus pneumoniae, the role of this gene in Streptococcus pyogenes has not been completely investigated. Therefore, to the best of our knowledge, we established the first mef(A)-knockout strain using an emm1-type S. pyogenes strain, and tested its susceptibility to erythromycin, clarithromycin and azithromycin. We found that the antimicrobial susceptibilities were almost identical to those of the parental strain. Hence, we established a knockout strain for another gene, msr(D), that is located immediately downstream of mef(A). The macrolide resistances of the resulting strain significantly decreased, and were further altered when both mef(A) and msr(D) were knocked out. The introduction of the msr(D) gene into a macrolide-sensitive strain conferred more resistance than the introduction of the mef(A) gene. The erythromycin susceptibilities of knockout strains were further dissected using two additional emm4- and emm75-type S. pyogenes strains. We found almost identical results for both strains except for the mef(A) knockout emm4 type, whose susceptibility was altered, although the change was less than that for the msr(D) knockout. These results suggest that both mef(A) and msr(D) are involved in macrolide resistance in S. pyogenes, and that the msr(D) gene plays a more predominant role in macrolide resistance than mef(A).
authors.affiliation: Department of Bacteriology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.|Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Bacteriology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Tatsuno
authors.affiliation: Department of Bacteriology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Okada
authors.affiliation: Department of Microbiology, Nagoya City University Hospital, Nagoya, Japan.
authors.forename: Nanako
authors.initials: N
authors.lastname: Hata
authors.affiliation: Department of Microbiology and Medical Zoology, Aichi Prefectural Institute of Public Health, Nagoya, Japan.
authors.forename: Masakado
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Department of Bacteriology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Isaka
authors.affiliation: Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Ken-Ichi
authors.initials: KI
authors.lastname: Isobe
authors.affiliation: Department of Bacteriology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Tadao
authors.initials: T
authors.lastname: Hasegawa
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D024881:Drug Resistance, Bacterial; D006801:Humans; D007564:Japan; D018942:Macrolides / Q000494:pharmacology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008826:Microbial Sensitivity Tests; D013290:Streptococcal Infections / Q000382:microbiology*; D013297:Streptococcus pyogenes / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D018942:Macrolides; C117866:MefA protein, Streptococcus; D008565:Membrane Proteins