Epidemiologic, Phenotypic, and Structural Characterization of Aminoglycoside-Resistance Gene aac(3)-IV.
Epidemiologic, Phenotypic, and Structural Characterization of Aminoglycoside-Resistance Gene aac(3)-IV.
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DOI：
10.3390/ijms21176133
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发表时间：
2020-08-25
影响因子：
5.6
通讯作者：
Hobbie SN
中科院分区：
文献类型：
--
作者：
Plattner M;Gysin M;Haldimann K;Becker K;Hobbie SN
氨基糖苷类抗生素是一种强大的杀菌治疗药物，常用于治疗严重的革兰氏阴性全身感染。然而，抗生素耐药性的出现和全球蔓延，在一定程度上损害了氨基糖苷类药物的临床应用，其影响程度与所有其他抗生素药物类别相似。目前正在临床开发的候选药物阿帕霉素被认为是下一代氨基糖苷类抗生素，对所有其他标准护理氨基糖苷类具有最小的交叉耐药。在此，我们分析了NCBI国家抗生素耐药生物数据库（NDARO）中591,140个病原体基因组，以注释阿帕霉素耐药基因，并将其与碳青霉烯类耐药和16S-rRNA甲基转移酶（RMTase）基因的基因型流行率进行了比较。发现3- n-乙酰转移酶基因aac(3)-IV是唯一具有临床相关性的阿帕霉素耐药基因，平均患病率为0.7%，比RMTase基因低4倍。在碳青霉烯酶阳性分离株的重要亚群中，aac(3)-IV的流行率比RMTase基因低9倍。经筛选的临床分离株和表达aac(3)-IV基因的重组菌株的表型分析证实，它们不仅对阿帕霉素耐药，而且对庆大霉素、妥布霉素和帕罗霉素耐药。通过对乙酰转移酶AAC(3)-IV中氨基糖苷结合囊的位点定向诱变来探究这种底物混杂的结构-活性关系，发现与His124、Glu185和Asp187的分子接触在与阿帕霉素和庆大霉素的结合中同样重要，而发现Asp67是一种区别性接触。我们的研究结果表明，临床分离株对阿帕霉素氨基糖苷交叉耐药仅限于单个基因的底物混杂，这使得阿帕霉素在碳青霉烯类和氨基糖苷类耐药细菌感染的覆盖范围方面是同类最佳的。
Aminoglycoside antibiotics are powerful bactericidal therapeutics that are often used in the treatment of critical Gram-negative systemic infections. The emergence and global spread of antibiotic resistance, however, has compromised the clinical utility of aminoglycosides to an extent similar to that found for all other antibiotic-drug classes. Apramycin, a drug candidate currently in clinical development, was suggested as a next-generation aminoglycoside antibiotic with minimal cross-resistance to all other standard-of-care aminoglycosides. Here, we analyzed 591,140 pathogen genomes deposited in the NCBI National Database of Antibiotic Resistant Organisms (NDARO) for annotations of apramycin-resistance genes, and compared them to the genotypic prevalence of carbapenem resistance and 16S-rRNA methyltransferase (RMTase) genes. The 3-N-acetyltransferase gene aac(3)-IV was found to be the only apramycin-resistance gene of clinical relevance, at an average prevalence of 0.7%, which was four-fold lower than that of RMTase genes. In the important subpopulation of carbapenemase-positive isolates, aac(3)-IV was nine-fold less prevalent than RMTase genes. The phenotypic profiling of selected clinical isolates and recombinant strains expressing the aac(3)-IV gene confirmed resistance to not only apramycin, but also gentamicin, tobramycin, and paromomycin. Probing the structure–activity relationship of such substrate promiscuity by site-directed mutagenesis of the aminoglycoside-binding pocket in the acetyltransferase AAC(3)-IV revealed the molecular contacts to His124, Glu185, and Asp187 to be equally critical in binding to apramycin and gentamicin, whereas Asp67 was found to be a discriminating contact. Our findings suggest that aminoglycoside cross-resistance to apramycin in clinical isolates is limited to the substrate promiscuity of a single gene, rendering apramycin best-in-class for the coverage of carbapenem- and aminoglycoside-resistant bacterial infections.
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DOI：
10.1016/j.ijantimicag.2020.106019
发表时间：
2020-07-01
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