Université catholique de Louvain, Louvain Drug Research Institute, Pharmacologie Cellulaire et Moléculaire, avenue E. Mounier 73, UCL B1.73.05, 1200 Brussels, Belgium.
Université Grenoble Alpes/CNRS, Département de Pharmacochimie Moléculaire, rue de la Chimie, F-38041 Grenoble, France.
Biochim Biophys Acta Biomembr. 2019 Oct 1;1861(10):182998. doi: 10.1016/j.bbamem.2019.05.020. Epub 2019 May 31.
Amphiphilic aminoglycoside derivatives are potential new antimicrobial agents mostly developed to fight resistant bacteria. The mechanism of action of the 3',6-dinonyl neamine, one of the most promising derivative, has been investigated on Gram-negative bacteria, including P. aeruginosa. In this study, we have assessed its mechanism of action against Gram-positive bacteria, S. aureus and B. subtilis. By conducting time killing experiments, we assessed the bactericidal effect induced by 3',6-dinonyl neamine on S. aureus MSSA and MRSA. By measuring the displacement of BODIPY™-TR cadaverine bound to lipoteichoic acids (LTA), we showed that 3',6-dinonyl neamine interacts with these bacterial surface components. We also highlighted the ability of 3',6-dinonyl neamine to enhance membrane depolarization and induce membrane permeability, by using fluorescent probes, DiSCC(5) and propidium iodide, respectively. These effects are observed for both MSSA and MRSA S. aureus as well as for B. subtilis. By electronic microscopy, we imaged the disruption of membrane integrity of the bacterial cell wall and by fluorescence microscopy, we demonstrated changes in the localization of lipids from the enriched-septum region and the impairment of the formation of septum. At a glance, we demonstrated that 3',6-dinonyl neamine interferes with multiple targets suggesting a low ability of bacteria to acquire resistance to this agent. In turn, the amphiphilic neamine derivatives are promising candidates for development as novel multitarget therapeutic antibiotics.
两亲性氨基糖苷衍生物是一类有潜力的新型抗菌药物，主要用于对抗耐药菌。其中最有前途的衍生物之一——3'，6-二壬基正胺的作用机制已在包括铜绿假单胞菌在内的革兰氏阴性菌中进行了研究。在本研究中，我们评估了其对革兰氏阳性菌金黄色葡萄球菌和枯草芽孢杆菌的作用机制。通过进行时间杀伤实验，我们评估了 3'，6-二壬基正胺对金黄色葡萄球菌 MSSA 和 MRSA 的杀菌作用。通过测量 BODIPY™-TR 腐胺与脂磷壁酸（LTA）结合的位移，我们表明 3'，6-二壬基正胺与这些细菌表面成分相互作用。我们还使用荧光探针 DiSCC（5）和碘化丙啶分别显示了 3'，6-二壬基正胺增强膜去极化和诱导膜通透性的能力。这些效应在 MSSA 和 MRSA 金黄色葡萄球菌以及枯草芽孢杆菌中均观察到。通过电子显微镜，我们可以观察到细胞膜完整性的破坏，通过荧光显微镜，我们可以证明富含隔膜区域的脂质定位发生变化，并损害隔膜的形成。总之，我们证明 3'，6-二壬基正胺干扰多个靶标，表明细菌获得对该药物耐药性的能力较低。反过来，两亲性正胺衍生物是开发新型多靶治疗抗生素的有前途的候选药物。
