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

Gustavo Penteado Battesini Carretero, Greice Kelle Viegas Saraiva, Magali Aparecida Rodrigues, Sumika Kiyota, Marcelo Porto Bemquerer, Hernan Chaimovich*, Iolanda Midea Cuccovia*

*Corresponding author

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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 α-helical conforma-tion 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 α-helical structure. Membrane surface high peptide/lipid ratios trig-gered 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.
OriginalsprogEngelsk
Artikelnummer542
TidsskriftBiomolecules
Vol/bind11
Udgave nummer4
Antal sider20
ISSN2218-273X
DOI
StatusUdgivet - 8 apr. 2021
Udgivet eksterntJa

Bibliografisk note

Funding Information:
Funding: This research was funded by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), grant number 2013/08166-5, 2015/10411-3, 2014/50983-3, 2018/15230-5; Conselho Na-cional de Desenvolvimento Científico e Tecnológico (CNPq), grant number 465259/2014-6, 301907/2019-6, 457733/2014-4; Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), grant number 23038.004630/2014-35, 88887.137085/2017-00; Conselho Nacional de Desen-volvimento Científico e Tecnológico, grant number 401187/2014-4, 141260/2017-3.

Emneord

  • Antimicrobial peptide
  • Biological activity
  • BP100
  • Calorimetry
  • Model membranes
  • Naphthalimide
  • Spectroscopy

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