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Sugar-based bactericides targeting phosphatidylethanolamine-enriched membranes.

ABSTRACT: 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.

SUBMITTER: Dias C

PROVIDER: S-EPMC6242839 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Sugar-based bactericides targeting phosphatidylethanolamine-enriched membranes.

Dias Catarina C Pais João P JP Nunes Rafael R Blázquez-Sánchez Maria-Teresa MT Marquês Joaquim T JT Almeida Andreia F AF Serra Patrícia P Xavier Nuno M NM Vila-Viçosa Diogo D Machuqueiro Miguel M Viana Ana S AS Martins Alice A Santos Maria S MS Pelerito Ana A Dias Ricardo R Tenreiro Rogério R Oliveira Maria C MC Contino Marialessandra M Colabufo Nicola A NA de Almeida Rodrigo F M RFM Rauter Amélia P AP

Nature communications 20181119 1

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 ...[more]

PMID: 30451842

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Project description:The translocation of apocytochrome c (apocyt.c) across large unilamellar vesicles (LUVs) constructed from mixtures of anionic and zwitterionic phospholipids, phosphatidylethanolamine (PE) and phosphatidylcholine (PC), has been studied. It was shown that the import ratio of horse heart apocyt.c in LUVs composed of phosphatidic acid (PA) combined with PE and PC (62+/-10%) was much higher than that in LUVs made of PE and PC plus any other acidic phospholipid species (20+/-5%). This feature was shared by tuna heart and chicken heart apocyt.c. In addition, the greater efficiency of the PA/PE/PC system versus others in facilitating apocyt.c translocation was maintained using synthetic anionic phospholipids with the same acyl chains. Besides, apocyt.c induces more leakage of entrapped fluorescein sulphonate (FS) from the interior of PA/PC/PE vesicles compared with phosphatidylglycerol (PG)/PC/PE ones. By measuring the intrinsic fluorescence emission spectrum and the accessibility of the preprotein to the fluorescence quencher, acrylamide, differences could be detected in the conformational changes of apocyt.c as a consequence of its interaction with PA/PE/PC and PG/PE/PC vesicles, respectively. Particularly notable is that PE is indispensable for the PA/PE/PC system to most efficiently facilitate apocyt.c translocation across the model membranes. With the fraction of PE increasing from 0 to 30 mol%, the translocation efficiency of apocyt.c as well as its ability to induce FS efflux was significantly enhanced in PA-containing LUVs, whereas this was not observed in the case of replacement of PA by PG or phosphatidylserine. It is also interesting to note that in LUVs containing PA, dioleoyl-PE, but not dielaidoyl-PE, can exert such influences, indicative of the role of non-bilayer formation propensity. On the basis of these results it is postulated that PA might increase the bilayer-destabilizing effects of PE, and hence increase the translocation efficiency of apocyt.c and its leakage-induction ability.

Dataset Information

Sugar-based bactericides targeting phosphatidylethanolamine-enriched membranes.

Publications

Sugar-based bactericides targeting phosphatidylethanolamine-enriched membranes.

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