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.