School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
Biomolecules. 2024 Feb 22;14(3):261. doi: 10.3390/biom14030261.
Small molecules that can restore the action of legacy antibiotics toward drug-resistant bacteria represent an area of ongoing research interest. We have previously reported indole-3-glyoxylamido and indole-3-acetamido-polyamine conjugates that exhibit intrinsic activity toward bacterial and fungal species, and the ability to enhance the action of doxycycline toward the Gram-negative bacteria ; however, these desirable activities were commonly associated with unfavorable cytotoxicity and/or red blood cell hemolytic properties. In this paper, we report the synthesis and biological investigation of a new class of α,ω-di(indole-3-carboxamido)polyamine derivatives, leading to the identification of several analogues that exhibit antimicrobial- and antibiotic-potentiating activities without detectable cytotoxic or hemolytic properties. 5-Bromo-substituted indole analogues and - were generally more broad-spectrum in their activity than others in the set, with (polyamine PA-3-6-3) being particularly notable for its anti-, , and activities (MIC ≤ 0.28 µM). The same analogue also restored the action of doxycycline toward with a 21-fold enhancement, while the corresponding 5-bromo-indole-3-carboxamide-PA3-7-3 analogue was able to enhance the action of both doxycycline and erythromycin toward and , respectively. The analogue was capable of disrupting the bacterial membrane of both and methicillin-resistant (MRSA) and the outer membrane of , suggesting that membrane perturbation could be a mechanism of action of both intrinsic antimicrobial activities and antibiotic potentiation.
能够恢复针对耐药菌的传统抗生素作用的小分子是目前正在研究的一个领域。我们之前已经报道过吲哚-3-糖基酰胺和吲哚-3-乙酰氨基-多胺缀合物，它们对细菌和真菌具有内在活性，并且能够增强多西环素对革兰氏阴性菌的作用；然而，这些理想的活性通常与不利的细胞毒性和/或红细胞溶血特性相关。在本文中，我们报告了一类新型的α，ω-二（吲哚-3-羧酰胺）多胺衍生物的合成和生物学研究，从而鉴定出几种具有抗菌和增强抗生素作用而无明显细胞毒性或溶血特性的类似物。5-溴取代的吲哚类似物 和 - 在其活性方面比该组中的其他类似物更为广谱，其中 （多胺 PA-3-6-3）因其对 、 和 的活性（MIC ≤ 0.28 µM）而尤为突出。同一类似物还恢复了多西环素对 的作用，增强了 21 倍，而相应的 5-溴-吲哚-3-羧酰胺-PA3-7-3 类似物能够增强多西环素和红霉素对 和 的作用。类似物 能够破坏 和耐甲氧西林金黄色葡萄球菌（MRSA）的细菌膜以及 的外膜，这表明膜扰动可能是内在抗菌活性和增强抗生素作用的一种作用机制。
