Abstract:
Globally, infections due to multi-drug resistant (MDR) Gram-negative bacterial (GNB) pathogens are on the rise, negatively impacting morbidity and mortality, necessitating urgent treatment alternatives. Herein, we report a detailed bio-evaluation of an ultrashort, cationic lipopeptide \'SVAP9I\' that demonstrated potent antibiotic activity and acted as an adjuvant to potentiate existing antibiotic classes towards GNBs. Newly synthesized lipopeptides were screened against ESKAPE pathogens and cytotoxicity assays were performed to evaluate the selectivity index (SI). SVAP9I exhibited broad-spectrum antibacterial activity against critical MDR-GNB pathogens including members of Enterobacteriaceae (MIC 4-8 mg/L), with a favorable CC50 value of ≥100 mg/L and no detectable resistance even after 50th serial passage. It demonstrated fast concentration-dependent bactericidal action as determined via time-kill analysis and also retained full potency against polymyxin B-resistant E. coli, indicating distinct mode of action. SVAP9I targeted E. coli\'s outer and inner membranes by binding to LPS and phospholipids such as cardiolipin and phosphatidylglycerol. Membrane damage resulted in ROS generation, depleted intracellular ATP concentration and a concomitant increase in extracellular ATP. Checkerboard assays showed SVAP9I\'s synergism with narrow-spectrum antibiotics like vancomycin, fusidic acid and rifampicin, potentiating their efficacy against MDR-GNB pathogens, including carbapenem-resistant Acinetobacter baumannii (CRAB), a WHO critical priority pathogen. In a murine neutropenic thigh infection model, SVAP9I and rifampicin synergized to express excellent antibacterial efficacy against MDR-CRAB outcompeting polymyxin B. Taken together, SVAP9I\'s distinct membrane-targeting broad-spectrum action, lack of resistance and strong in vitro andin vivopotency in synergism with narrow spectrum antibiotics like rifampicin suggests its potential as a novel antibiotic adjuvant for the treatment of serious MDR-GNB infections.
摘要:
全球范围内,多药耐药(MDR)革兰氏阴性细菌(GNB)病原体引起的感染正在上升,对发病率和死亡率产生负面影响,需要紧急治疗替代方案。在这里,我们报告了对超短机的详细生物评估,阳离子脂肽“SVAP9I”显示出有效的抗生素活性,并充当佐剂以增强现有抗生素类别对GNBs的作用。针对ESKAPE病原体筛选新合成的脂肽,并进行细胞毒性测定以评估选择性指数(SI)。SVAP9I对关键的MDR-GNB病原体(包括肠杆菌科成员)具有广谱抗菌活性(MIC4-8mg/L),具有≥100mg/L的良好CC50值,即使在第50次连续通过后也没有可检测到的电阻。它显示了通过时间杀灭分析确定的快速浓度依赖性杀菌作用,并且还保留了对多粘菌素B抗性大肠杆菌的全部效力。表明不同的行动模式。SVAP9I通过与LPS和磷脂如心磷脂和磷脂酰甘油结合而靶向大肠杆菌的外膜和内膜。膜损伤导致ROS产生,细胞内ATP浓度减少,细胞外ATP随之增加。棋盘分析显示SVAP9I与万古霉素等窄谱抗生素的协同作用,夫西地酸和利福平,增强它们对MDR-GNB病原体的功效,包括耐碳青霉烯类鲍曼不动杆菌(CRAB),世卫组织关键优先病原体。在小鼠中性粒细胞减少大腿感染模型中,SVAP9I和利福平协同表达对MDR-CRAB的优异抗菌功效,胜过多粘菌素B。SVAP9I具有独特的膜靶向广谱作用,在与利福平等窄谱抗生素的协同作用中,缺乏耐药性和强大的体外和体内效力,这表明其作为治疗严重MDR-GNB感染的新型抗生素佐剂的潜力。