Sugar-based bactericides targeting phosphatidylethanolamine-enriched membranes. Issue 1 (December 2018)

• Record Type: Journal Article
• Authors: Dias, Catarina; Pais, João; Nunes, Rafael; Blázquez-Sánchez, Maria-Teresa; Marquês, Joaquim; Almeida, Andreia; Serra, Patrícia; Xavier, Nuno; Vila-Viçosa, Diogo; Machuqueiro, Miguel; Viana, Ana; Martins, Alice; Santos, Maria; Pelerito, Ana; Dias, Ricardo; Tenreiro, Rogério; Oliveira, Maria; Contino, Marialessandra; Colabufo, Nicola; Almeida, Rodrigo; Rauter, Amélia
• Is Part Of: Nature communications. Volume 9:Issue 1(2018)
• Page Start: 1
• Page End: 12
• Publication Date: 2018-12
• Subjects: Biology -- Periodicals; Physical sciences -- Periodicals; 505
• DOI: 10.1038/s41467-018-06488-4
• Languages: English
• ISSNs: 2041-1723

Abstract

Abstract Anthrax is an infectious disease caused byBacillus 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 overB. anthracis andBacillus 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. Bacillus anthracis causes the infectious disease anthrax. Here, the authors synthesized deoxy glycosides that are effective againstB. anthracis and related bacteria and found that these amphiphilic compounds kill bacteria via an unusual mechanism of action.