Biomimetic Antibiotics - Synthesis and Characterization of Antibiotic Polymers with Low Resistance Development Potential
Final Report Abstract
The aim of this project was to prepare synthetic polymers with antimicrobial properties. This biomimetic approach was based on the observation that many organisms produce antimicrobial peptides (AMPs), which have broad-spectrum antimicrobial activity, while the cells of the host organism are less affected due to differences in their membrane charge and lipid composition. As the synthesis of natural AMPs based on amino acids is complicated, their application as pharmaceuticals is limited and a simplified approach to obtain such molecules based on synthetic polymers is highly desirable. While still capturing the key features of AMPs (amphiphilicity and positive charge), synthetic AMPs (SMAMPs) can be obtained and up-scaled more easily. In this project, polymers based on poly(norbornenes) were synthesized and characterized. A highly simplified ‘molecular construction kit’ for the synthesis of SMAMPs with tailor-made properties was developed. The antimicrobial activity of these polymers was tuned by varying the amphiphilicity of the norbornene monomers as well as the comonomer composition, the SMAMP molecular weight, the counter ion and the effective charge. The biological properties of these SMAMPs were determined using the minimum inhibitory concentration (MIC) and the hemolytic concentration (HC) assay. Thus, SMAMPs with a previously unprecedented selectivity (=MIC/HC) were discovered. Additionally, certain SMAMP copolymers with a double selectivity for Gram positive over Gram negative bacteria were discovered. The interaction of these polymers with model membranes and modified bacteria were studied. It was thus found that the double selectivity was not due to binding to lipopolysaccharide or peptidoglycan, but due to the double membrane structure of Gram negative bacteria. A SMAMP with astonishing selectivity for MRSA (multiple resistant S. aureus), a pathogen widespread in hospitals, was also discovered. Future research will focus on incorporating such SMAMPs on surfaces used for medical devices to prevent MRSA spread in medical settings.
Publications
- Antimicrobial Polymers Prepared by ROMP with Unprecedented Selectivity: A Molecular Construction Kit Approach. J. Am. Chem. Soc. 2008, 130, 9836
K. Lienkamp, A. E. Madkour, A. Musante, C. F. Nelson, K. Nüsslein, G. N. Tew
- Water Soluble Poly(ethyleneoxide) Functionalized Norbornene Polymers. J. Polymer Sci. A, Polymer Chem. 2008, 46, 2640
S. F. Alfred, Z. Al-Badri, A. E. Madkour, K. Lienkamp, G. N. Tew
- Water-soluble ROMP Polymers From Aminefunctionalized Norbornenes. J. Polymer Sci. A, Polymer Chem. 2008, 46, 6672
S. F. Alfred, K. Lienkamp, A. E. Madkour, G. N. Tew
- Antimicrobial Polymers Prepared by Ring-Opening Metathesis Polymerization: Influencing Antimicrobial Properties By Charge Density Variation and Ion Exchange. Chem. Eur. J., 2009, 15, 11715
K. Lienkamp, A. E. Madkour, K.-N. Kumar, K. Nüsslein, G. N. Tew
- Doubly Selective Antimicrobial Polymers – How Do They Differentiate Between Bacteria? Chem. Eur. J. 2009, 15, 11710
K. Lienkamp, K.-N. Kumar, A. Som, K. Nüsslein, G. N. Tew
- Synthetic Mimics of Antimicrobial Peptides – A Versatile ROMP-based Platform for the Synthesis of Selective Antibacterial and Cell Penetrating Polymers. Chem. Eur. J., 2009, 15, 11784
K. Lienkamp, G. N. Tew
- Water-soluble Polymers from Acid- Functionalized Norbornenes. J. Polymer Sci. A, Polymer Chem., 2009, 47, 1266-1273
K. Lienkamp, C. F. Kins, S. F. Alfred, A. E. Madkour, G. N. Tew
