Inhibition of Enzymatic Acetylation-Mediated Resistance to Plazomicin by Silver Ions.
Inhibition of Enzymatic Acetylation-Mediated Resistance to Plazomicin by Silver Ions.
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DOI：
10.3390/ph16020236
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发表时间：
2023-02-03
期刊：
影响因子：
--
通讯作者：
Tolmasky ME
中科院分区：
文献类型：
--
作者：
Ngo D;Magaña AJ;Tran T;Sklenicka J;Phan K;Eykholt B;Jimenez V;Ramirez MS;Tolmasky ME
普拉佐霉素是最近美国食品和药物管理局（FDA）批准的半合成氨基糖苷类。其结构由通过在N1位添加2（S）-羟基氨基丁酰基和在6′位添加羟乙基取代基修饰的西索米星支架组成。这些取代产生了一种对大多数氨基糖苷类修饰酶具有抗性的分子。该组中识别普拉佐霉素作为底物的主要酶是Ia型氨基糖苷2′-N-乙酰转移酶[AAC（2′）-Ia]，其降低抗生素的效力。设计将抗微生物剂与耐药性抑制剂结合的联合收割机是延长现有抗生素使用寿命的公认策略。我们最近发现几种金属离子抑制氨基糖苷6′-N-乙酰转移酶Ib [AAC（6′）-Ib]介导的许多氨基糖苷类的酶失活。特别是，Ag+也通过其他机制增强氨基糖苷类的作用，在干扰AAC（6′）-Ib介导的对阿米卡星的耐药性方面非常有效。在此我们报道了银醋酸盐是体外AAC（2′）-Ia介导的普拉佐霉素乙酰化的有效抑制剂，它降低了携带aac（2′）-Ia的大肠杆菌的耐药性水平。当结构基因在天然或blaTEM-1启动子的控制下表达时，抗性回复试验产生等同的结果。普拉佐霉素与银组合的抗生素作用是杀菌的，并且该混合物对人胚肾293（HEK 293）细胞没有显示出显著的毒性。
Plazomicin is a recent U.S. Food and Drug Administration (FDA)-approved semisynthetic aminoglycoside. Its structure consists of a sisomicin scaffold modified by adding a 2(S)-hydroxy aminobutyryl group at the N1 position and a hydroxyethyl substituent at the 6′ position. These substitutions produced a molecule refractory to most aminoglycoside-modifying enzymes. The main enzyme within this group that recognizes plazomicin as substrate is the aminoglycoside 2′-N-acetyltransferase type Ia [AAC(2′)-Ia], which reduces the antibiotic’s potency. Designing formulations that combine an antimicrobial with an inhibitor of resistance is a recognized strategy to extend the useful life of existing antibiotics. We have recently found that several metal ions inhibit the enzymatic inactivation of numerous aminoglycosides mediated by the aminoglycoside 6′-N-acetyltransferase type Ib [AAC(6′)-Ib]. In particular, Ag+, which also enhances the effect of aminoglycosides by other mechanisms, is very effective in interfering with AAC(6′)-Ib-mediated resistance to amikacin. Here we report that silver acetate is a potent inhibitor of AAC(2′)-Ia-mediated acetylation of plazomicin in vitro, and it reduces resistance levels of Escherichia coli carrying aac(2′)-Ia. The resistance reversion assays produced equivalent results when the structural gene was expressed under the control of the natural or the blaTEM-1 promoters. The antibiotic effect of plazomicin in combination with silver was bactericidal, and the mix did not show significant toxicity to human embryonic kidney 293 (HEK293) cells.
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DOI：
10.1093/jac/dkab352
发表时间：
2021-11-22
期刊：
The Journal of antimicrobial chemotherapy
影响因子：
--
作者：
Bassetti M;Garau J
通讯作者：
Garau J
影响因子：
3.6
作者：
Herisse, Marion;Duverger, Yohann;Ezraty, Benjamin
通讯作者：
Ezraty, Benjamin
AAC（2'）酶对下一代氨基糖苷的抗性的结构和系统发育分析。
影响因子：
4.6
作者：
Bassenden AV;Dumalo L;Park J;Blanchet J;Maiti K;Arya DP;Berghuis AM
通讯作者：
Berghuis AM
影响因子：
3.8
作者：
GRAHAM, FL;SMILEY, J;NAIRN, R
通讯作者：
NAIRN, R
DOI：
10.1007/s101560050001
发表时间：
1999-03-01
期刊：
Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy
影响因子：
--
作者：
Kondo, S.;Hotta, Kunimoto
通讯作者：
Hotta, Kunimoto