Naphthalimide-Containing BP100 Leads to Higher Model Membranes Interactions and Antimicrobial Activity

Author(s)

Carretero, Gustavo Penteado Battesini ^[1] ; Saraiva, Greice Kelle Viegas ^[1] ; Rodrigues, Magali Aparecida ^[1] ; Kiyota, Sumika ^[2] ; Bemquerer, Marcelo Porto ^[3] ; Chaimovich, Hernan ^[1] ; Cuccovia, Iolanda Midea ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Quim, Dept Bioquim, BR-05508000 Sao Paulo, SP - Brazil

^[2] Inst Biol, Lab Bioquim Prot & Peptideos, BR-04014002 Sao Paulo, SP - Brazil

^[3] Empresa Brasileira Pesquisa Agr, Embrapa Recursos Genet & Biotecnol, Parque Estacao Biol, BR-70770900 Brasilia, DF - Brazil

• Document type: Journal article
• Source: BIOMOLECULES; v. 11, n. 4 APR 2021.
• Web of Science Citations: 0

Abstract

In a large variety of organisms, antimicrobial peptides (AMPs) are primary defenses against pathogens. BP100 (KKLFKKILKYL-NH2), a short, synthetic, cationic AMP, is active against bacteria and displays low toxicity towards eukaryotic cells. BP100 acquires a alpha-helical conformation upon interaction with membranes and increases membrane permeability. Despite the volume of information available, the action mechanism of BP100, the selectivity of its biological effects, and possible applications are far from consensual. Our group synthesized a fluorescent BP100 analogue containing naphthalimide linked to its N-terminal end, NAPHT-BP100 (Naphthalimide-AAKKLFKKILKYL-NH2). The fluorescence properties of naphthalimides, especially their spectral sensitivity to microenvironment changes, are well established, and their biological activities against transformed cells and bacteria are known. Naphthalimide derived compounds are known to interact with DNA disturbing related processes as replication and transcription, and used as anticancer agents due to this property. A wide variety of techniques were used to demonstrate that NAPHT-BP100 bound to and permeabilized zwitterionic POPC and negatively charged POPC:POPG liposomes and, upon interaction, acquired a alpha-helical structure. Membrane surface high peptide/lipid ratios triggered complete permeabilization of the liposomes in a detergent-like manner. Membrane disruption was driven by charge neutralization, lipid aggregation, and bilayer destabilization. NAPHT-BP100 also interacted with double-stranded DNA, indicating that this peptide could also affect other cellular processes besides causing membrane destabilization. NAPHT-BP100 showed increased antibacterial and hemolytic activities, compared to BP100, and may constitute an efficient antimicrobial agent for dermatological use. By conjugating BP100 and naphthalimide DNA binding properties, NAPHT-BP100 bound to a large extent to the bacterial membrane and could more efficiently destabilize it. We also speculate that peptide could enter the bacteria cell and interact with its DNA in the cytoplasm. (AU)

• FAPESP's process: 18/15230-5 - Antibacterial and anticancer activities of BP100 peptide and analogs containing Naphathalimide
• Grantee: Gustavo Penteado Battesini Carretero
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 14/50983-3 - INCT 2014: complex fluids
• Grantee: Antonio Martins Figueiredo Neto
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 13/08166-5 - Interfacial chemistry: drugs, peptides and ezymes interactions with membrane models
• Grantee: Iolanda Midea Cuccovia
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 15/10411-3 - Multi-User Equipment, previously approved in grant 2015/08166-5: stopped-flow
• Grantee: Iolanda Midea Cuccovia
• Support Opportunities: Multi-user Equipment Program