Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA.
Division of STD Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, U.S. Department of Health and Human Services, Atlanta, Georgia, USA.
mBio. 2018 Nov 27;9(6):e02281-18. doi: 10.1128/mBio.02281-18.
Recent reports suggest that mosaic-like sequences within the (ultiple ransferable esistance) efflux pump locus of , likely originating from commensal sp. by transformation, can increase the ability of gonococci to resist structurally diverse antimicrobials. Thus, acquisition of numerous nucleotide changes within the gene encoding the transcriptional repressor (MtrR) of the efflux pump-encoding operon or overlapping promoter region for both along with those that cause amino acid changes in the MtrD transporter protein were recently reported to decrease gonococcal susceptibility to numerous antimicrobials, including azithromycin (Azi) (C. B. Wadsworth, B. J. Arnold, M. R. A. Satar, and Y. H. Grad, mBio 9:e01419-18, 2018, https://doi.org/10.1128/mBio.01419-18). We performed detailed genetic and molecular studies to define the mechanistic basis for why such strains can exhibit decreased susceptibility to MtrCDE antimicrobial substrates, including Azi. We report that a strong -acting transcriptional impact of a single nucleotide change within the -35 hexamer of the promoter as well gain-of-function amino acid changes at the C-terminal region of MtrD can mechanistically account for the decreased antimicrobial susceptibility of gonococci with a mosaic-like locus. Historically, after introduction of an antibiotic for treatment of gonorrhea, strains of emerge that display clinical resistance due to spontaneous mutation or acquisition of resistance genes. Genetic exchange between members of the genus occurring by transformation can cause significant changes in gonococci that impact the structure of an antibiotic target or expression of genes involved in resistance. The results presented here provide a framework for understanding how mosaic-like DNA sequences from commensal that recombine within the gonococcal efflux pump locus function to decrease bacterial susceptibility to antimicrobials, including antibiotics used in therapy of gonorrhea.
最近的报告表明，淋病奈瑟菌（Neisseria gonorrhoeae）多重耐药（MDR）外排泵基因座内的镶嵌序列可能来源于共生的奈瑟菌属（Neisseria），通过转化增加淋病奈瑟菌对结构多样的抗菌药物的耐药能力。因此，最近报道了编码外排泵操纵子转录抑制剂（MtrR）的 mtrR 基因或重叠启动子区域内的大量核苷酸变化以及导致 MtrD 转运蛋白氨基酸变化的核苷酸变化，这些变化使淋病奈瑟菌对包括阿奇霉素（Azi）在内的多种抗菌药物的敏感性降低（C. B. Wadsworth、B. J. Arnold、M. R. A. Satar 和 Y. H. Grad，mBio 9:e01419-18, 2018, https://doi.org/10.1128/mBio.01419-18）。我们进行了详细的遗传和分子研究，以确定为什么这些菌株对 MtrCDE 抗菌底物（包括 Azi）表现出较低的敏感性的机制基础。我们报告称，单个核苷酸变化在 启动子的 -35 六聚体中的强转录作用以及 MtrD 羧基末端区域的功能获得性氨基酸变化可以从机制上解释具有镶嵌样 基因座的淋病奈瑟菌对抗生素敏感性降低的原因。历史上，在引入用于治疗淋病的抗生素后，由于自发突变或获得耐药基因，淋病奈瑟菌会出现具有临床耐药性的菌株。通过转化发生的奈瑟菌属成员之间的遗传交换会导致淋病奈瑟菌发生重大变化，从而影响抗生素靶标结构或参与耐药的基因表达。这里提出的结果为理解来自共生的镶嵌样 DNA 序列如何在淋病奈瑟菌的外排泵基因座内重组以降低细菌对抗生素的敏感性，包括治疗淋病中使用的抗生素，提供了一个框架。
