Rational design of antimicrobial peptides targeting Gram-negative bacteria |
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| Institution: | 1. CIQUP, Centro de Investigação em Química, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Porto, Portugal;2. Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS), Departamento de Química Orgánica, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain;3. Faculty of Pharmacy, Comenius University in Bratislava, 832 32 Bratislava, Slovak Republic;4. iBB – Institute for Bioengineering and Biosciences, Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal;5. Department of Chemistry and Biochemistry, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal;1. Department of Biophysics, Bose Institute, EN 80, Sector V, Bidhan Nagar, Kolkata 700091, India;2. Prof Brien Holden Eye Research Centre, L V Prasad Eye Institute, Hyderabad-500034, India;3. School of Life Science, University of Technology Sydney, Ultimo, NSW 2007, Australia;4. Department of Biology, The University of Texas Rio Grande Valley, Edinburg, TX 78539, USA;5. School of Optometry and Vision Science, University of New South Wales, Sydney, Australia;6. Optometry and Vision Science Research Group, Aston University, UK;7. Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032. India;8. Department of Physics, Bose Institute, Kolkata 700009, India;9. Seoul National University of Science and Technology, Seoul 01811, Republic of Korea |
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| Abstract: | Membrane-targeting host antimicrobial peptides (AMPs) can kill or inhibit the growth of Gram-negative bacteria. However, the evolution of resistance among microbes poses a substantial barrier to the long-term utility of the host AMPs. Combining experiment and molecular dynamics simulations, we show that terminal carboxyl capping enhances both membrane insertion and antibacterial activity of an AMP called P1. Furthermore, we show that a bacterial strain with evolved resistance to this peptide becomes susceptible to P1 variants with either backbone capping or lysine-to-arginine substitutions. Our results suggest that cocktails of closely related AMPs may be useful in overcoming evolved resistance. |
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| Keywords: | Antimicrobial peptide Molecular dynamic simulation Peptide-membrane interactions Toxicity |
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