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Aminoglycoside 6′-N-acetyltransferase Type Ib [AAC(6′)-Ib]-Mediated Aminoglycoside Resistance: Phenotypic Conversion to Susceptibility by Silver Ions
Antibiotics ( IF 4.3 ) Pub Date : 2020-12-31 , DOI: 10.3390/antibiotics10010029
Craig M. Reeves , Jesus Magallon , Kenneth Rocha , Tung Tran , Kimberly Phan , Peter Vu , Yang Yi , Crista L. Oakley-Havens , José Cedano , Verónica Jimenez , Maria S. Ramirez , Marcelo E. Tolmasky

Clinical resistance to amikacin and other aminoglycosides is usually due to the enzymatic acetylation of the antimicrobial molecule. A ubiquitous resistance enzyme among Gram-negatives is the aminoglycoside 6′-N-acetyltransferase type Ib [AAC(6′)-Ib], which catalyzes acetylation using acetyl-CoA as a donor substrate. Therapies that combine the antibiotic and an inhibitor of the inactivation reaction could be an alternative to treat infections caused by resistant bacteria. We previously observed that metal ions such as Zn2+ or Cu2+ in complex with ionophores interfere with the AAC(6′)-Ib-mediated inactivation of aminoglycosides and reduced resistance to susceptibility levels. Ag1+ recently attracted attention as a potentiator of aminoglycosides′ action by mechanisms still in discussion. We found that silver acetate is also a robust inhibitor of the enzymatic acetylation mediated by AAC(6′)-Ib in vitro. This action seems to be independent of other mechanisms, like increased production of reactive oxygen species and enhanced membrane permeability, proposed to explain the potentiation of the antibiotic effect by silver ions. The addition of this compound to aac(6′)-Ib harboring Acinetobacter baumannii and Escherichia coli cultures resulted in a dramatic reduction of the resistance levels. Time-kill assays showed that the combination of silver acetate and amikacin was bactericidal and exhibited low cytotoxicity to HEK293 cells.

中文翻译:

Ib型氨基糖苷6'-N-乙酰基转移酶[AAC(6')-Ib]介导的氨基糖苷抗性:表型转化为银离子的敏感性

临床上对丁胺卡那霉素和其他氨基糖苷类药物的耐药性通常归因于抗微生物分子的酶促乙酰化作用。革兰氏阴性菌中普遍存在的抗性酶是氨基糖苷6'- N-乙酰基转移酶Ib [AAC(6')-Ib],它以乙酰基-CoA为供体底物催化乙酰化。结合抗生素和灭活反应抑制剂的疗法可能是治疗由耐药菌引起的感染的替代方法。我们以前观察到与离子载体复合的金属离子,例如Zn 2+或Cu 2+,会干扰AAC(6')-Ib介导的氨基糖苷的失活并降低对药敏度的抵抗力。银1+最近,仍在讨论中的机制作为氨基糖苷作用的增强剂引起了人们的关注。我们发现醋酸银也是体外AAC(6')-Ib介导的酶促乙酰化的强力抑制剂。该作用似乎与其他机制无关,例如增加了活性氧的产生和膜通透性的提高,被认为可以解释银离子对抗生素作用的增强作用。将该化合物添加到具有鲍曼不动杆菌大肠杆菌培养物的aac(6')-Ib导致耐药性水平显着降低。时间杀伤试验表明,乙酸银和丁胺卡那霉素的组合具有杀菌作用,并且对HEK293细胞显示出低细胞毒性。
更新日期:2020-12-31
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