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Biologic and Materials Sciences and Division of Prosthodontics

Background information

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Bacteria are becoming increasingly resistant to traditional antibiotics.  This is now causing hospital infections which lead to 90,000 death each year in the United States.  Current antibiotic drugs operate by inhibiting the reproduction enzymes in bacteria, thus preventing growth of a bacterial colony.  Through mutation, bateria are able to attack the enzyme inhibitors and continue reproducing.  Although a constant barrage of new antibiotic drugs can solve the problem temporarily, a novel solution is more desirable. 

Looking to nature for inspiration, we find that natural defense peptides protect the body from harmful bacteria by a different mechanism: membrane disruption.  The peptides induce the formation of pores in bacteria cell membranes, which leads to leakage of cell contents and ultimately to cell death.  There is no evidence that bacteria are capable of developing a resistance to peptides.  Hence, a viable solution might be to synthesize molecules which mimic the structure of peptides.  In fact, this has already been successfully done.  However, the preperation of these materials is too costly and labor-intensive to be practical for industry-scale production.

The next development was the relatively facile synthesis of simple polymer derivatives with some attributes similar to peptides.  Peptides are facially amphiphilic, meaning that they have hydrophobic and cationic side chains on opposite faces of a helix.  Inexpensive, easy-to-make amphiphilic polymers have been developed which exhbit good antimicrobial properties.  So the problem is totally solved now?  Not exactly.  These new polymers are also quite effective at puncturing the membranes of human red blood cells, i.e., they are toxic.  This obviously limits their potential for use in medicinal applications.

In the Kuroda lab, we aim to capture the essence of peptide activity in a polymer.  Our design criteria are low toxicity for medicinal applications, low cost, and easy synthesis.  There has already been some headway in the area.  As a post-doc at UPenn, Kenichi and his advisor, Prof. William DeGrado, synthesized copolymers of butyl methacrylate and cationic aminoethyl methacrylate using mercaptopropionate as the chain transfer agent (to control molecular weight).  The synthesis of these materials is illustrated in the scheme below.

 

pmma_derivatives.bmp


The polymers shown above have shown strong efficacy against bacteria, which is quantified as the Minimum Inhibitory Concentration (MIC), which is the lowest concentration of polymer which inhibits the growth of the bacteria.  Efficacy against human red blood cells is measured as the concentration of polymer needed to kill 50% of the human red bloods in a solution, the HC50.  When the HC50 is greater than the MIC, we catagorize the material as a nontoxic antimicrobial.  In the figure below, values of MIC and HC50 are shown.  From A to C, the molecular weight of the copolymers vary from 10,100 g/mol to  1,300 g/mol.  In part C, for lower than 20% butyl methacrylate (hydrophobic) groups, the HC50 is notably higher than the MIC.  This is a promising result, but it only scratches the surface of what we wish to know!

 

mic_hc50.bmp



In the "Reserach Areas" section of this site, you will find breif descriptions of our ongoing efforts.