Bioinspired polymer-peptide conjugates based on maximin H5 for infection control in medical devices

Abstract

The global emergence of antibiotic-resistant pathogens is a public health crisis claiming 700,000 lives annually, with future projections suggesting an increase to 10 million deaths by the year 2050. This doctoral thesis offers a novel solution by implementing biomolecular strategies to combat this threat. The main objective of this research has been the use of the anionic and C-terminally modified antimicrobial peptide, MH5C-Cys, and its bioconjugate MH5C-Cys-PEG 5 kDa, for the prevention and treatment of bacterial biofilms and infectious diseases, without harming human cells. Employing human microvascular endothelial cells (HMVECs) as a model of host tissue, key marker proteins such as VE-Cadherin and F-actin were studied to determine changes in molecular and physiological function and inflammation. Advanced techniques such as SDS-PAGE and LCMS/MS - Peptide Mass Fingerprinting were used, revealing the presence of Fibulin-1 during treatment with MH5C-Cys and its bioconjugate, indicating optimal cell adhesion and extension functioning.<br /> <br /> Similarly, human erythrocytes were examined, reflecting the importance of this model in mimicking host cells for future clinical applications and safety in the development of potential pharmaceutical treatments. In vitro studies revealed morphological changes and a minimal hemolysis percentage, demonstrating that modifications at the C-terminal end of MH5C-Cys optimize interaction with cell membranes, reducing the risk of cell lysis and effects of serum proteases. Focusing on catheter-associated urinary tract infections (CAUTIs), the functionalization of the catheter surface with MH5C-Cys and MH5C-Cys-PEG was characterized, demonstrating its effective antimicrobial activity by immobilizing the peptide on the catheter surface, which was confirmed using techniques such as ATR- FTIR, SEM, EDS, and XPS. Detailed analysis of C1s, O1s, N1s, and S2p atoms provided information on the bonds and mechanisms of incorporation of these biomolecules. Additionally, the durability of these surfaces and their antimicrobial activity were evaluated over time, maintaining their effectiveness on the surface for up to a month. This research highlights the potential of antimicrobial peptides in the fight against antibiotic resistance and infectious diseases, offering innovative perspectives for therapeutic strategies and clinical microbiology. A significant advance is presented towards innovative solutions that could reshape the paradigm of CAUTIs treatment and other nosocomial infections.