Sklenicka Jan, Tran Tung, Ramirez Maria S, Donow Haley M, Magaña Angel J, LaVoi Travis, Mamun Yasir, Jimenez Verónica, Chapagain Prem, Santos Radleigh, Pinilla Clemencia, Giulianotti Marc A, Tolmasky Marcelo E
Center for Applied Biotechnology Studies, Department of Biological Science, College of Natural Sciences and Mathematics, California State University Fullerton, Fullerton, CA 92831, USA.
Center for Translational Science, Florida International University, Port St. Lucie, FL 34987, USA.
Antibiotics (Basel). 2024 Jul 19;13(7):672. doi: 10.3390/antibiotics13070672.
Resistance to amikacin and other major aminoglycosides is commonly due to enzymatic acetylation by the aminoglycoside 6'--acetyltransferase type I enzyme, of which type Ib [AAC(6')-Ib] is the most widespread among Gram-negative pathogens. Finding enzymatic inhibitors could be an effective way to overcome resistance and extend the useful life of amikacin. Small molecules possess multiple properties that make them attractive for drug development. Mixture-based combinatorial libraries and positional scanning strategy have led to the identification of a chemical scaffold, pyrrolidine pentamine, that, when substituted with the appropriate functionalities at five locations (R1-R5), inhibits AAC(6')-Ib-mediated inactivation of amikacin. Structure-activity relationship studies have shown that while truncations to the molecule result in loss of inhibitory activity, modifications of functionalities and stereochemistry have different effects on the inhibitory properties. In this study, we show that alterations at position R1 of the two most active compounds, and , reduced inhibition levels, demonstrating the essential nature not only of the presence of an -phenyl moiety at this location but also the distance to the scaffold. On the other hand, modifications on the R3, R4, and R5 positions had varied effects, demonstrating the potential for optimization. A correlation analysis between molecular docking values (ΔG) and the dose required for two-fold potentiation of the compounds described in this and the previous studies showed a significant correlation between ΔG values and inhibitory activity.
对阿米卡星和其他主要氨基糖苷类药物的耐药性通常是由于氨基糖苷类6'-乙酰转移酶I型酶的酶促乙酰化作用，其中Ib型[AAC(6')-Ib]在革兰氏阴性病原体中最为普遍。寻找酶抑制剂可能是克服耐药性并延长阿米卡星使用寿命的有效方法。小分子具有多种特性，使其在药物开发中具有吸引力。基于混合物的组合文库和位置扫描策略已导致鉴定出一种化学支架——吡咯烷五胺，当在五个位置（R1-R5）用适当的官能团取代时，它可抑制AAC(6')-Ib介导的阿米卡星失活。构效关系研究表明，虽然分子截短会导致抑制活性丧失，但官能团和立体化学的修饰对抑制特性有不同影响。在本研究中，我们表明，两种最具活性的化合物 和 在R1位置的改变降低了抑制水平，这不仅证明了该位置存在对映体苯基部分的必要性，还证明了其与支架的距离的重要性。另一方面，R3、R4和R5位置的修饰产生了不同的效果，表明存在优化的潜力。分子对接值（ΔG）与本研究及先前研究中所述化合物两倍增效所需剂量之间的相关性分析表明，ΔG值与抑制活性之间存在显著相关性。
