Mihaela Bacalum1, Lorant Janosi2, Florina Zorila3, Ana-Maria Tepes4, Cristina Ionescu5, Elena Bogdan4, Niculina Hadade4, Liviu Craciun5, Ion Grosu4, Ioan Turcu6, Mihai Radu7. 1. Department of Life and Environmental Physics, Horia Hulubei National Institute for Physics and Nuclear Engineering, Reactorului 30, PO Box MG-6, Măgurele 077125, Romania. 2. Molecular and Biomolecular Physics Department, National Institute for Research and Development of Isotopic and Molecular Technologies, 65-103 Donath Street, 400293 Cluj-Napoca, Romania. 3. Multipurpose Irradiation Facility Center, Horia Hulubei National Institute for Physics and Nuclear Engineering, Reactorului 30, PO Box MG-6, Măgurele 077125, Romania. 4. Babeş-Bolyai University, Supramolecular Organic and Organometallic Chemistry Center (SOOMCC), Cluj-Napoca, 11 Arany Janos Street, 400028 Cluj-Napoca, Romania. 5. Applied Nuclear Physics Department, Horia Hulubei National Institute for Physics and Nuclear Engineering, Reactorului 30, PO Box MG-6, Măgurele 077125, Romania. 6. Molecular and Biomolecular Physics Department, National Institute for Research and Development of Isotopic and Molecular Technologies, 65-103 Donath Street, 400293 Cluj-Napoca, Romania. Electronic address: ioan.turcu@itim-cj.ro. 7. Department of Life and Environmental Physics, Horia Hulubei National Institute for Physics and Nuclear Engineering, Reactorului 30, PO Box MG-6, Măgurele 077125, Romania. Electronic address: mradu@nipne.ro.
Abstract
BACKGROUND: High antimicrobial efficacy of short tryptophan-and arginine-rich peptides makes them good candidates in the fight against pathogens. Substitution of tryptophan and arginine by histidine could be used to modulate the peptides efficacy by optimizing their structures. METHODS: The peptide (RRWWRWWRR), reported to showed good antimicrobial efficacy, was used as template, seven new analogs being designed substituting tryptophan or arginine with histidine. The peptides' efficacy was tested against E. coli, B. subtilis and S. aureus. The cytotoxicity and hemolytic effect were evaluated and the therapeutic index was inferred for each peptide. Atomic force microscopy and molecular simulation were used to analyze the effects of peptides on bacterial membrane. RESULTS: The substitution of tryptophan by histidine proved to strongly modulate the antimicrobial activity, mainly by changing the peptide-to-membrane binding energy. The substitution of arginine has low effect on the antimicrobial efficacy. The presence of histidine residue reduced the cytotoxic and hemolytic activity of the peptides in some cases maintaining the same efficacy against bacteria. The peptides' antimicrobial activity was correlated to the 3D-hydrophobic moment and to a simple structure-based packing parameter. CONCLUSION: The results show that some of these peptides have the potential to become good candidates to fight against bacteria. The substitution by histidine proved to fine tune the therapeutic index allowing the optimization of the peptide structure mainly by changing its binding energy and 3D-hydrophobic moment. GENERAL SIGNIFICANCE: The short tryptophan reach peptides therapeutic index can be maximized using the histidine substitution to optimize their structure.
BACKGROUND: High antimicrobial efficacy of short tryptophan-and arginine-rich peptides makes them good candidates in the fight against pathogens. Substitution of tryptophan and arginine by histidine could be used to modulate the peptides efficacy by optimizing their structures. METHODS: The peptide (RRWWRWWRR), reported to showed good antimicrobial efficacy, was used as template, seven new analogs being designed substituting tryptophan or arginine with histidine. The peptides' efficacy was tested against E. coli, B. subtilis and S. aureus. The cytotoxicity and hemolytic effect were evaluated and the therapeutic index was inferred for each peptide. Atomic force microscopy and molecular simulation were used to analyze the effects of peptides on bacterial membrane. RESULTS: The substitution of tryptophan by histidine proved to strongly modulate the antimicrobial activity, mainly by changing the peptide-to-membrane binding energy. The substitution of arginine has low effect on the antimicrobial efficacy. The presence of histidine residue reduced the cytotoxic and hemolytic activity of the peptides in some cases maintaining the same efficacy against bacteria. The peptides' antimicrobial activity was correlated to the 3D-hydrophobic moment and to a simple structure-based packing parameter. CONCLUSION: The results show that some of these peptides have the potential to become good candidates to fight against bacteria. The substitution by histidine proved to fine tune the therapeutic index allowing the optimization of the peptide structure mainly by changing its binding energy and 3D-hydrophobic moment. GENERAL SIGNIFICANCE: The short tryptophan reach peptides therapeutic index can be maximized using the histidine substitution to optimize their structure.
Authors: Lavinia L Ruta; Ileana C Farcasanu; Mihaela Bacalum; Mina Răileanu; Arpad Mihai Rostas; Constantin Daniliuc; Mariana Carmen Chifiriuc; Luminița Măruțescu; Marcela Popa; Mihaela Badea; Emilia Elena Iorgulescu; Rodica Olar Journal: Molecules Date: 2021-11-09 Impact factor: 4.411