The Low-Alkalinity Polymyxin Derivative, AL-6, Shows High Activity Against Multidrug-Resistant Acinetobacter baumannii Clinical Isolates In Vitro and A. baumannii ATCC 19606 In Vivo: Preliminary Analysis of the Antibacterial Mechanism.

Abstract

Polymyxin B and colistin (polymyxin E) are increasingly used as the last line of therapy for infections caused by multidrug-resistant (MDR) gram-negative pathogens. However, nephrotoxicity is still a limiting factor for the use of polymyxin. Therefore, better tolerated and more effective polymyxin derivatives are urgently needed. In this study, we aimed to evaluate the activity of the low-alkalinity polymyxin derivative, AL-6, against MDR Acinetobacter baumannii (Ab) clinical isolates in vitro and A. baumannii ATCC 19606 in vivo. Additionally, we performed a preliminarily study of the antibacterial mechanism. AL-6 showed much higher activity (0.125-0.25 μg/mL) against MDR A. baumannii clinical isolates than polymyxin E2 (PE2, 0.5-1 μg/mL). AL-6 also showed much higher activity (0.5-256 μg/mL) against polymyxin-resistant strains than PE2 (16-1024 μg/mL). Additionally, AL-6 showed slow resistance against A. baumannii. AL-6 also increased the survival rates of mice by 10% at 48 h compared with PE2 (5 mg/kg). AL-6 could be used at a dose of up to 10 mg/kg, increasing the survival rate to 30% at 72 h after infection. A preliminary study of the antibacterial mechanism showed that AL-6 permeabilized the outer membrane and destroyed cell membrane integrity. Moreover, there was a substantial increase in zeta potential (i.e., less negative) upon AL-6 exposure for A. baumannii. Overall, AL-6 carrying only four positive charges showed high activity against A. baumannii in vitro by disrupting cell membrane integrity. Higher doses of AL-6 could increase survival rates of mice. Thus, AL-6 may have potential applications as a bactericidal agent.