Antibiofilm and antivirulence properties of 6-polyaminosteroid derivatives against antibiotic-resistant bacteria

The emergence of multi-drug resistant pathogens is a major public health problem, leading to rethink and innovate in our bacterial control strategies. Here, we explore the anti-biofilm and anti-virulence activities of nineteen 6-polyaminosterol derivatives (squalamine-based), presenting a modulation of their polyamine side chain, on 4 major pathogens, i.e. carbapenem-resistant A. baumannii (CRAB) and P. aeruginosa (CRPA), a methicillin-resistant S. aureus (MRSA) and a vancomycin-resistant E. faecium (VRE) strains. We screened the effect of these derivatives on biofilm formation and eradication. 4e (for CRAB, VRE and MRSA) and 4f (for all the strains) were the most potent one and displayed activities as good as conventional antibiotics. We also identified 11 compounds able to decrease by more than 40% the production of pyocyanin, a major virulence factor of P. aeruginosa. We demonstrated that 4f treatment acts against bacterial infections in Galleria mellonella and significantly prolonged the larvae survival (from 50% to 80%) after 24 h of CRAB, VRE and MRSA infections. As shown by proteomic studies, 4f triggered distinct cellular responses depending on the bacterial species, but essentially related to the cell envelop. Its interesting anti-biofilm and anti-virulence properties make it promising candidate for use in therapeutics.

多药耐药病原体的出现是重大公共卫生问题，促使我们重新思考并创新细菌控制策略。本研究探讨了十九种6-聚氨基甾醇衍生物（基于角鲨胺）对四种主要病原体的抗生物膜和抗毒力活性，这些衍生物的聚胺侧链经过修饰；所述病原体包括碳青霉烯耐药鲍曼不动杆菌（CRAB）、碳青霉烯耐药铜绿假单胞菌（CRPA）、耐甲氧西林金黄色葡萄球菌（MRSA）及耐万古霉素屎肠球菌（VRE）菌株。我们筛选了这些衍生物对生物膜形成与清除的影响。衍生物4e（针对CRAB、VRE及MRSA）和4f（针对所有菌株）表现出最强活性，其效果与传统抗生素相当。我们还发现11种化合物可使铜绿假单胞菌的主要毒力因子绿脓菌素的产量降低40%以上。我们证实，4f处理对大蜡螟的细菌感染具有抑制作用，在CRAB、VRE及MRSA感染24小时后，显著提高了幼虫存活率（从50%升至80%）。蛋白质组学研究表明，4f可根据细菌种类触发不同的细胞反应，但本质上均与细胞包膜相关。其优异的抗生物膜和抗毒力特性使其成为极具潜力的治疗候选药物。