Bismuth Phosphinates in Bi-Nanocellulose Composites and their Efficacy towards Multi-Drug Resistant Bacteria.

A series of poorly soluble phenyl bis-phosphinato bismuth(III) complexes [BiPh(OP(=O)R1 R2 )2 ] (R1 =R2 =Ph; R1 =R2 =p-OMePh; R1 =R2 =m-NO2 Ph; R1 =Ph, R2 =H; R1 =R2 =Me) have been synthesised and characterised, and shown to have effective antibacterial activity against Escherichia coli (E. coli), Staphylococcus aureus (S. aureus), methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). The bismuth complexes were incorporated into microfibrillated (nano-) cellulose generating a bismuth-cellulose composite as paper sheets. Antibacterial evaluation indicates that the Bi-cellulose materials have analogous or greater activity against Gram positive bacteria when compared with commercial silver based additives: silver sulfadiazine loaded at 0.43 wt % into nanocellulose produces a 10 mm zone of inhibition on the surface of agar plates containing S. aureus whereas [BiPh(OP(=O)Ph2 )2 ] loaded at 0.34 wt % produces an 18 mm zone of inhibition. These phenyl bis-phosphinato bismuth(III) complexes show potential to be applied in materials in healthcare facilities, to inhibit the growth of bacteria capable of causing serious disease.

Aryl bismuth phosphinates [BiAr2(O(O)PRR')]: structure-activity relationships for antibacterial activity and cytotoxicity.

To study and evaluate the structure-activity relationships in di-aryl bismuth phosphinates on antibacterial activity and cytotoxicity a series of complexes containing ortho-methoxyphenyl, meta-methoxyphenyl, meta-tolyl and para-tolyl aryl groups; [Bi(o-MeOPh)2(O(O)P(H)Ph)]n1, [Bi(o-MeOPh)2(O(O)PPh2)]n2, [Bi(o-MeOPh)2(O(O)P(p-MeOPh)2)]n3, [Bi(m-MeOPh)2(O(O)P(H)Ph)]n4, [Bi(m-MeOPh)2(O(O)PPh2)]n5, [Bi(m-MeOPh)2(O(O)P(p-MeOPh)2)]n6, [Bi(m-tol)2(O(O)P(H)Ph)]n7, [Bi(m-tol)2(O(O)PPh2)]n8, [Bi(m-tol)2(O(O)P(p-MeOPh)2)]n9, [Bi(p-tol)2(O(O)P(H)Ph)]n10, [Bi(p-tol)2(O(O)PPh2)]n11 and [Bi(p-tol)2(O(O)P(p-MeOPh)2)]n12, were synthesised and characterised. Complexes 4, 7, 8, 10 and 11 were structurally authenticated by X-ray crystallography. Evaluation of their antibacterial activity towards methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), Escherichia coli (E. coli) and Pseudomonas aeruginosa (P. aeruginosa) showed that the bismuth bound aryl group has a profound influence on activity, with the o-MeOPh complexes 1-3 showing very little activity while the m-MeOPh complexes have the greatest activity towards MRSA and VRE in the range of 0.63 to 1.25 µM. Viability studies with Cos-7 cells showed that the di-aryl bismuth complexes 1-12 are less cytotoxic than their di-phenyl bismuth analogues, with a general trend of toxicity observed as p-tolyl > m-tolyl > m-methoxyphenyl > o-methoxyphenyl. The large difference in Cos-7 viability for complexes 1 (IC50 > 80 µM) and 4 (IC50 14.0 µM) was further investigated through bismuth uptake studies, where there was no obvious difference in Cos-7 bismuth uptake at 5 µM. This suggests that the bismuth-bound aryl group has a significant impact on biological activity, which is then further mediated by other ligands.

Impact of structural changes in heteroleptic bismuth phosphinates on their antibacterial activity in Bi-nanocellulose composites.

To study and evaluate the effect of ligand choice and distribution in bismuth phosphinates on toxicity and antibacterial activity, a series of novel diphenyl mono-phosphinato bismuth complexes, [BiPh2(O(O[double bond, length as m-dash])P(H)Ph)] 1, [BiPh2(O(O[double bond, length as m-dash])PPh2)] 2, [BiPh2(O(O[double bond, length as m-dash])PMe2)] 3 and [BiPh2(O(O[double bond, length as m-dash])P(p-MeOPh)2)] 4, were synthesised, characterised and structurally authenticated by X-ray crystallography. Evaluation of their antibacterial activity towards Staphylococcus aureus (S. aureus), methicillin-resistant S. aureus (MRSA), vancomycin-resistant Enterococci (VRE), Escherichia coli (E. coli) and Pseudomonas aeruginosa (P. aeruginosa) showed all four mono-phosphinato bismuth complexes to be highly active. However, unlike their less soluble bis-phosphinato analogues, they displayed an increased level of toxicity towards mammalian cells (COS-7, human and murine fibroblasts), where it was shown the complexes disrupt cellular membranes leading to cytotoxicity. The mono-phosphinato bismuth complexes were used to produce antibacterial nanocellulose composites. Leaching studies showed that complex 1 had the highest levels of leaching, at 15% of the total available bismuth when the composite was soaked in water. The aqueous leachates of 1 were bacteriostatic towards MRSA and VRE at concentrations between 4.0 and 4.6 µM, while being bactericidal towards E. coli above 2.8 µM. At similar concentrations the complex showed toxicity towards human fibroblast cells, with cell viability reduced to 2% (1, 2.4 µM). The possibility to control leaching of the bismuth complexes from cellulose composites through structural changes is evidence for their potential application in antibacterial surfaces and materials.