Highly Preferentially Active Polymethacrylates As Mimics Of Antimicrobial Peptides

The emergence and spread of antibiotic-resistance pose a recent threat to global public health. To fight against antibiotic-resistance, one core strategy is to develop novel antimicrobial therapeutics. Antimicrobial peptides (AMPs), part of the innate immunity of multicellular organisms, have demonstrated wide-spectrum antimicrobial activity. Unlike conventional antibiotics which target the bacterial metabolic pathways, AMPs act by disrupting the bacterial cellular membranes, a generic mode which appears to be more difficult for bacteria to circumvent. Though widely viewed as a promising source of novel antimicrobial pharmaceutics, AMPs are labile to protease degradation and expensive to manufacture. Inspired by that most AMPs are simultaneously cationic and hydrophobic, researchers have developed a variety of synthetic mimetics of AMPs (SMAMPs). By being simultaneously cationic and hydrophobic, these SMAMPs have demonstrated similar in vitro actity as do AMPs. However, how to improve the selectivity-preferential activity against bacteria over mammalian cells-of AMPs and SMAMPs remains an ongoing challenge.In Chapter2of this dissertation, Since infected area mostly presents acid local environment, we designed and prepared acid-activated synthetic mimics of antimcirobial peptides (aSMAMPs), we varied the net charge of the polymer solution by different pH conditions. The antimicrobial activity of the aSMAMPs is activated at acidic pH but disappears at physiolygical pH. We achieved preferential activity we expected. Under the same experiment condition, traditional antimicrobials such as gentamicin have100weaker antimicrobial activity at pH5.0than at pH7.4.In Chapter3of this dissertation, we explored the possibility of hydrophilic-and-cationic polymer as an effective solution to achieve preferential antimicrobial activity. Based on the biostatistical analysis of397lysine-rich AMPs, we found that shorter antimicrobial peptide has higher average hydrophobicity. Using magaininⅡ as a prototypical long AMP, we found that its hydrophilic-and-cationic mutants permeabilized bacterial cellular membranes as did itself. These observations encouraged us to systematically examine whether hydrophilic-and-cationic mutants of long AMPs and SMAMPs offers a different pathway towards the desired preferential activity. By constructing a minimal prototypical family of molecules comprising polymer SMAMPs and corresponding hydrophilic-and-cationic mutants, we found that the hydrophobic moiety of polymer SMAMPs facilitated antibacterial activity but diminished in effectiveness as polymer chain length increased. Those long hydrophilic-and-cationic mutants also permeabilized bacterial membranes. Moreover, hemolysis assays showed that, compared to long polymer SMAMPs, the corresponding hydrophilic-and-cationic mutants demonstrated greatly reduced hemolytic toxity and, as a result, drastically enhanced selectivity. Taken together, our results suggest that long hydrophilic-and-cationic polymers may be a a simple but effective way towards the desired preferential activity.