Bis-Triphenyl Phosphonium-Based Nano Vesicles Demonstrated Potent and Selective Antibacterial Effects on Clinically Relevant Superbugs

The increasing emergence of multidrug resistant (MDR) pathogens, due to antibiotics misuse, leads to obstinate infections, with high morbidity and high-cost hospitalizations. To oppose these MDR superbugs, new antimicrobial options are necessary. Quaternary phosphonium salts (QPSs) have demonstrated appealing antibacterial properties, and a triphenyl phosphonium salt, recently reported by us, has shown excellent bacteriostatic effects against MDR isolates of Enterococcus and Staphylococcus genus. Here, aiming at finding new antibacterial devices active towards a broader spectrum of clinically relevant bacteria, responsible of severe human infections, we synthesized a water-soluble, sterically hindered quaternary phosphonium salt (BPPB). It incorporates two tri-phenyl phosphonium groups linked by a C12 alkyl chain, thus embodying the characteristics of molecules known as bola-amphiphiles, capable to self-forming spherical nano-vesicles in solution. BPPB was characterized by ATR-FTIR, NMR and UV spectroscopy, FIA-MS (ESI), elemental analysis and potentiometric titrations. DLS analyses evidenced spherical vesicles of about 45 nm in solution, having a positive zeta potential (+18 mV). For the first time, the antibacterial effects of BPPB were assessed against fifty clinical isolates of both Gram-positive and Gram-negative species. Exceptional antibacterial effects were observed on all strains tested, involving highly worrying species included in ESKAPE bacteria. The lowest MICs were 0.250 µg/mL, while the highest ones (32 µg/mL) were those observed on MDR Gram-negative metallo-β-lactamase-producing bacteria and/or species resistant also to colistin, carbapenems, cefiderocol, so that intractable with current available antibiotics. Moreover, when administered to HepG2 human hepatic and COS-7 monkey kidney cells, BPPB showed very high selectivity for all Gram-positive isolated tested and for clinically relevant Gram-negative superbugs such as S. maltophylia, A. baumannii and E. coli, thus being very promising to be clinically developed.