Document details

Sugar-based bactericides targeting phosphatidylethanolamine-enriched membranes

Author(s): Dias, Catarina ; Pais, João P. ; Nunes, Rafael ; Blázquez-Sánchez, Maria-Teresa ; Marquês, Joaquim T. ; Almeida, Andreia F. ; Serra, Patrícia ; Xavier, Nuno M. ; Vila-Viçosa, Diogo ; Machuqueiro, Miguel ; Viana, Ana S. ; Martins, Alice ; Santos, Maria S. ; Pelerito, Ana ; Dias, Ricardo ; Tenreiro, Rogério ; Oliveira, Maria C. ; Contino, Marialessandra ; Colabufo, Nicola A. ; de Almeida, Rodrigo F.M. ; Rauter, Amélia P.

Date: 2018

Persistent ID:

Origin: Repositório Científico do Instituto Nacional de Saúde

Project/scholarship: info:eu-repo/grantAgreement/FCT/5876/147264/PT; info:eu-repo/grantAgreement/FCT/5876/147256/PT; info:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBPD%2F42567%2F2007/PT; info:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBDE%2F51998%2F2012/PT;

Subject(s): Anti-Bacterial Agents; Bacillus anthracis; Bacillus cereus; Caco-2 Cells; Carbohydrate Conformation; Cell Membrane; Cell Survival; Cell Wall; Glycosides; Humans; Kinetics; Lipid Bilayers; Microbial Sensitivity Tests; Microbial Viability; Phase Transition; Phosphatidylethanolamines; Structure-Activity Relationship


Anthrax is an infectious disease caused by Bacillus anthracis, a bioterrorism agent that develops resistance to clinically used antibiotics. Therefore, alternative mechanisms of action remain a challenge. Herein, we disclose deoxy glycosides responsible for specific carbohydrate-phospholipid interactions, causing phosphatidylethanolamine lamellar-to-inverted hexagonal phase transition and acting over B. anthracis and Bacillus cereus as potent and selective bactericides. Biological studies of the synthesized compound series differing in the anomeric atom, glycone configuration and deoxygenation pattern show that the latter is indeed a key modulator of efficacy and selectivity. Biomolecular simulations show no tendency to pore formation, whereas differential metabolomics and genomics rule out proteins as targets. Complete bacteria cell death in 10 min and cellular envelope disruption corroborate an effect over lipid polymorphism. Biophysical approaches show monolayer and bilayer reorganization with fast and high permeabilizing activity toward phosphatidylethanolamine membranes. Absence of bacterial resistance further supports this mechanism, triggering innovation on membrane-targeting antimicrobials.

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Document Type Journal article
Language English
Contributor(s) Dias, Catarina; Pais, João P.; Nunes, Rafael; Blázquez-Sánchez, Maria-Teresa; Marquês, Joaquim T.; Almeida, Andreia F.; Serra, Patrícia; Xavier, Nuno M.; Vila-Viçosa, Diogo; Machuqueiro, Miguel; Viana, Ana S.; Martins, Alice; Santos, Maria S.; Pelerito, Ana; Dias, Ricardo; Tenreiro, Rogério; Oliveira, Maria C.; Contino, Marialessandra; Colabufo, Nicola A.; de Almeida, Rodrigo F.M.; Rauter, Amélia P.
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