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.
Bis-Triphenyl Phosphonium-Based Nano Vesicles Demonstrated Potent and Selective Antibacterial Effects on Clinically Relevant Superbugs
Alfei S.;Zuccari G.
2024-01-01
Abstract
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.