Bactericidal Dendritic Polycation Cloaked with Stealth Material via Lipase-Sensitive Intersegment Acquires Neutral Surface Charge without Losing Membrane-Disruptive Activity

Abstract

Net cationicity of membrane-disruptive antimicrobials is necessary for their activity but may elicit immune attack when administered intravenously. By cloaking a dendritic polycation (G2) with poly(caprolactone-b-ethylene glycol) (PCL-b-PEG), we obtain a nanoparticle antimicrobial, G2-g-(PCL-b-PEG), which exhibits neutral surface charge but kills >99.9% of inoculated bacterial cells at ≤8 μg/mL. The observed activity may be attributed PCL's responsive degradation by bacterial lipase and the consequent exposure of the membrane-disruptive, bactericidal G2 core. Moreover, G2-g-(PCL-b-PEG) exhibits good colloidal stability in the presence of serum and insignificant hemolytic toxicity even at ≥2048 μg/mL. suggesting good blood compatibility required for intravenous administration.

Long-subchain hyperbranched poly(aminoethyl acrylate): A potent antimicrobial polymer with low hemolytic toxicity

“…Propargyl 2,2‐bis((2′‐bromo‐2′‐methyl‐propanoyloxy)methyl) propionate (PBMPMP) and 2‐(( tert ‐butoxycarbonyl)amino)ethyl acrylate (Boc‐AEA) and tris(2‐(dimethyl‐amino)ethyl)amine (Me 6 TREN) was prepared according to the procedure described in the literatures . Di‐ tert ‐butyl dicarbonate ((Boc) 2 O), 2,2‐bis(hydroxymethyl)propionic acid, 2,2‐dimethoxypropane, acryloyl chloride, propargyl alcohol, 4‐dimethylaminopyridine, and α ‐bromoisobutyryl bromide were purchased from Aladdin and used as received.…”

“…An alternative strategy toward selective activity are hydrophilic‐and‐cationic mutants of long AMPs or polymeric SMAMPs, suggesting that hydrophobicity may be dispensable when the antimicrobial molecules are long enough . Based on this strategy, polycationic long‐subchain dendrimer has been developed and demonstrated selective activity against bacterial over mammalian membranes, suggesting that hyperbranched polymers may mimic the membrane‐disruptive activity mode of AMPs as do their linear counterparts. Long‐subchain dendrimers have highly ordered architectures, uniform subchains, relatively narrow polydispersity and well‐controlled sizes; nevertheless, their preparation are generally effort‐consuming: involving multiple‐step reaction, requiring repeated purification, and offering limited yield of final products .…”

“…Based on this strategy, polycationic long‐subchain dendrimer has been developed and demonstrated selective activity against bacterial over mammalian membranes, suggesting that hyperbranched polymers may mimic the membrane‐disruptive activity mode of AMPs as do their linear counterparts. Long‐subchain dendrimers have highly ordered architectures, uniform subchains, relatively narrow polydispersity and well‐controlled sizes; nevertheless, their preparation are generally effort‐consuming: involving multiple‐step reaction, requiring repeated purification, and offering limited yield of final products . In contrast to long‐subchain dendrimers, long‐subchain hyper‐branched polymers with uniform subchains could be achieved via easy polycondensation of seesaw‐type AB 2 macromonomers, particularly suitable for large‐scale production .…”

Quaternized and Thiazole‐Functionalized Free Radical‐Generating Organometallic Dendrimers as Antimicrobial Platform against Multidrug‐Resistant Microorganisms

“…It is posited that the presence of different antimicrobial agents in these hybrids leads to multiple mechanisms of antimicrobial activity that could mitigate the evolution of resistance since it is more challenging for microorganisms to deal with multiple mechanisms of action . Many reports feature this approach in combating resistance as evidenced by numerous examples of dual action, bioconjugates or hybrid antimicrobial macromolecules and materials . For this approach to succeed, the hybrid is expected to exert superior activity over its constituent agents .…”

“…The synthesis route to the target hybrids involves initial synthesis of the antimicrobial dendrimers using the complex and subsequent functionalization of these dendrimers with quaternary ammonium groups or 2‐mercaptobenzothiazole. Functionalizing dendrimers with antimicrobial agents is a well‐investigated strategy to combat resistance; however, to the best of our knowledge, functionalizing an antimicrobial dendrimer with antimicrobial agents to obtain a hybrid represents a more promising though a yet‐to‐be investigated strategy.…”