Antibiotic resistance has become one of the greatest challenges in treating bacterial infections in healthcare. Inspired by the structures of bacteriainvading viruses and antimicrobial peptides (AMPs), we hypothesize that in addition to a balance of amphiphilicity and electropositivity, nanostructure is another important structural determinant that defines how membraneactive antibiotics remodel host membranes to gain desirable activity and selectivity. Here we study the structure-activity relationship of a series of polymer molecular brushes (PMBs) with well-defined nanostructures that mimic spherical and rod-shaped viruses. Our preliminary data based on PMBs with hydrophilic polymer brushes reveal that: (1) amphiphilicity is not a required trait-hydrophilic PMBs can be designed to have potent antibiotic performance as well with negligible hemolytic activity; (2) the nanoscale architecture of PMBs defines their double selectivity, not molecular weight per se; (3) PMBs are far more powerful antibiotics than individual linear-chain polymers that make up the PMBs; and (4) nanostructured PMBs induce topological changes of membranes by forming membrane pores that unlikely fit in with any known models of AMP action. These findings expand existing wisdom on designing synthetic mimics of AMPs and suggest that the spatially-defined, multivalent interactions inherent to nanostructured PMBs is of great significance for the development of new membrane-active antibiotics.
Laser irradiation has developed into a novel technique of non-invasive stimulation in cardiac and neural tissues. However, physical parameters for the laser irradiation-induced cardiac contractions have not been clarified, because various physicochemical reactions, such as photochemical and photothermal effects, are triggered in this process. Here we studied the effects of laserinduced local temperature changes on the functions of isolated cardiomyocytes. We demonstrated previously that a microscopic heat pulse (DT = 0.2 C for 2 sec) induces a Ca 2þ burst in cancer cells (HeLa cells) at a body temperature (Tseeb et al., HFSP J., 2009), with the mechanism similar to that of rapid cooling contracture in skeletal and cardiac muscles. In the present study, we generated microscopic heat pulses by focusing infrared laser light in extracellular solution near adult rat cardiomyocytes. We found that a microscopic heat pulse (DT = 5 C for 0.5 sec) induces contractions at basal temperature of 36 C. At 25 C, larger DT was required to induce contractions. When 2.5 Hz heat pulses were repeatedly applied, we observed oscillatory contractions of cardiomyocytes. Different from contractions induced by electric stimulation, Ca 2þ transients were not detected during the contraction. Likewise, heat pulses induced contractions of skinned cardiomyocytes in Ca 2þ-free solution in the presence of ATP. These results demonstrate that heat pulses can regulate cardiac contractions without any involvement of Ca 2þ dynamics, by directly activating the actomyosin interaction. Hence, our microheating technique may be useful for stimulating the beating of failing hearts without causing abnormal Ca 2þ dynamics.
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