Surprising Antibacterial Activity and Selectivity of Hydrophilic Polyphosphoniums Featuring Sugar and Hydroxy Substituents

Abstract

There is currently an urgent need for the development of new antibacterial agents to combat the spread of antibiotic-resistant bacteria. We explored the synthesis and antibacterial activities of novel, sugar-functionalized phosphonium polymers. While these compounds exhibited antibacterial activity, we unexpectedly found that the control polymer poly(tris(hydroxypropyl)vinylbenzylphosphonium chloride) showed very high activity against both Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus and very low haemolytic activity against red blood cells. These results challenge the conventional wisdom in the field that lipophilic alkyl substituents are required for high antibacterial activity and opens prospects for new classes of antibacterial polymers.

Antibacterial Activity of Polymers: Discussions on the Nature of Amphiphilic Balance

“…[8] Similarly,P alermo and co-workers reported selfimmolative poly(benzyl ether)s with pendant oligo(ethylene glycol) and thioether-linked primary amines,w hich are both nominally hydrophilic, whereas the backbone is intensely hydrophobic. [9] Like HydroxyP P ,while these polymers do lack pendant linear alkyl side chains,t hey do not lack amphiphilicity.Thus,wedonot want the final sentence of reference [1]: "This intriguing result challenges the hydrophilic/lipophilic balance previously thought to be required for antibacterial activity." to be misinterpreted.…”

“…At this stage,the mechanism of action of HydroxyP P has not yet been investigated. As suggested in reference [1],iti s possible that HydroxyP P acts by membrane disruption, or by an alternative mechanism. This can only be resolved through future experiments.F or example,i tw ill be important to quantify the hydrophobicity of the polymer directly using measurements such as HPLC retention times [10] and wateroctanol partition coefficients, [2q,9a] to probe the mechanism through experiments such as dye leakage from liposomes [2l,q-t,w, 10,11] and through electron microscopy.…”

“…Indeed, all of the above molecules exhibit amphiphilicity.F or example,a sn oted in reference [1] the hydrophobic polystyrene backbone and even the terminal reversible addition-fragmentation chain transfer (RAFT) group impart amphiphilicity to HydroxyP P . Thus,wewish to emphasize that the observations described in reference [1],and other recent examples,donot require us to abandon the idea of amphiphilic balance altogether.R ather, we think it is important to highlight that amphiphilic balance is not restricted to linear alkyls ide chains as the source of hydrophobicity. Previous polyphosphoniums reported by Endo and coworkers featured long,linear alkyl side chains that increased the hydrophobicity of the polymer chains to such an extent that the polymers indiscriminately lysed biomembranes by as urfactant-like mode of biocidal action.…”

Biodegradable Antibacterial Polymeric Nanosystems: A New Hope to Cope with Multidrug‐Resistant Bacteria

“…Although antibiotic‐containing nanosystems significantly enhance antibacterial efficacy and slow down the emergences of multidrug resistant superbugs, the development of new materials with intrinsic antibacterial activities is still in urgent demand. Over the recent decades, the developments of polymers with intrinsic antimicrobial moieties, such as quaternary ammonium (QA) groups, phosphonium groups, AMPs and their synthetic mimics, have attracted striking attention in the field of biomaterials. In a pioneer work, a series of biodegradable triblock copolymers were synthesized via ring‐opening polymerization, containing two hydrophobic poly(trimethylene carbonate) (PTMC) blocks to form the core of micelles, and quaternized bactericidal blocks to form the shell of the micelles, as shown in Figure .…”

Amphiphilic water soluble cationic ring opening metathesis copolymer as an antibacterial agent

“…Major limitation of such antimicrobial peptides are high manufacturing costs, short term antimicrobial ability and decomposition because of their low chemical stability under physiological condition . Whereas, synthetic polymer‐based mimic host defense peptides are generally more robust in physiological condition, easy to synthesize. It is also expected that they do not exhibit drug resistance like conventional antibiotics due to their membrane disruption mechanism .…”