FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2905049682> ?p ?o ?g. }

• W2905049682 abstract "The increasing appearance of multi-drug-resistant pathogenic bacteria to most available antibiotics is emerging as a global public health problem. Unfortunately, excessive use in both human and animal medicine has led to the emergence of multi-drug-resistant strains for most antibiotics available on the market. It is therefore urgent to better understand the underlying mechanisms by which bacteria resist to antibiotics to combat multi-resistance strains. In this context, this work aims at better understanding the molecular basis of active drug efflux in Pseudomonas aeruginosa, which is one of the most important mechanisms used by the bacterium to resist to several antibiotics. Efflux systems form protein complexes in the bacterial wall and actively expel antibiotics even before they reach their intracellular target, rendering them inactive. The structural study focuses on the MexA-MexB-OprM RND (Resistance-Nodulation and cell Division) system that is constitutively expressed in wild-type bacteria and is over-expressed in resistant strains. This tripartite complex is composed of a transporter inserted into the inner membrane, a channel protein inserted in the outer membrane and a periplasmic adapter protein that connects the other two proteins to form a sealed conduit through the periplasm. In the absence of knowledge of the structure of the tripartite complex, the aim of the thesis was to develop an original strategy to reconstitute the whole complex in vitro in a lipid environment from the three native components produced separately.The assembly of the tripartite complex is made by mixing MexA with MexB and OprM in Nanodisc mimicking the two lipid bilayers. The structure of this tripartite complex was obtained by combining cryo electron microscopy and the so-called 'isolated particles' approach. The three-dimensional structure of the complex, calculated at a resolution of less than 4 A, was used to build an atomic model of the tripartite complex assembled between two Nanodiscs. The tripartite complex is composed of an OprM trimer, a MexB trimer and a MexA hexamer surrounding MexB and interacting with OprM. We solve the complete structure of MexA whose N-terminal part hitherto unknown because of a high flexibility and describe for the first time the anchoring of MexA in a lipid membrane. The conformational changes are observed on OprM and MexB when they are assembled in the complex with the opening of the periplasmic end of OprM and the spatial re-orientation of a MexB loop to establish additional contact with MexA.To integrate this tripartite structure into the antibiotic efflux cycle, it describes a state that is probably a resting state, knowing that no specific ligand was added during assembly. In addition, the complex forms an open channel at its extracellular end, providing the conduit to evacuate the drugs carried by MexB that uses the proton motive force as a source of energy. This work opens new perspective for structural studies of other conformational states of the efflux system in energized conditions to fulfill our understanding of the efflux cycle mechanism. Moreover, the knowledge of this first tripartite native complex structure constitutes the first step towards the development of molecules capable of blocking the assembly of the complex for therapeutic uses. Indeed, such molecules would inhibit active efflux and restore the lost efficiency of current antibiotics." @default.
• W2905049682 created "2018-12-22" @default.
• W2905049682 creator A5081213501 @default.
• W2905049682 date "2018-11-26" @default.
• W2905049682 modified "2023-09-23" @default.
• W2905049682 title "Cryo-electron microscopy structural studies of a bacterial multi-drug efflux pump involved in antibiotic resistance" @default.
• W2905049682 hasPublicationYear "2018" @default.
• W2905049682 type Work @default.
• W2905049682 sameAs 2905049682 @default.
• W2905049682 citedByCount "0" @default.
• W2905049682 crossrefType "dissertation" @default.
• W2905049682 hasAuthorship W2905049682A5081213501 @default.
• W2905049682 hasConcept C104317684 @default.
• W2905049682 hasConcept C146587185 @default.
• W2905049682 hasConcept C151730666 @default.
• W2905049682 hasConcept C185592680 @default.
• W2905049682 hasConcept C200082930 @default.
• W2905049682 hasConcept C201663137 @default.
• W2905049682 hasConcept C2777637488 @default.
• W2905049682 hasConcept C2779343474 @default.
• W2905049682 hasConcept C501593827 @default.
• W2905049682 hasConcept C523546767 @default.
• W2905049682 hasConcept C54355233 @default.
• W2905049682 hasConcept C547475151 @default.
• W2905049682 hasConcept C55493867 @default.
• W2905049682 hasConcept C86803240 @default.
• W2905049682 hasConcept C89423630 @default.
• W2905049682 hasConcept C95444343 @default.
• W2905049682 hasConceptScore W2905049682C104317684 @default.
• W2905049682 hasConceptScore W2905049682C146587185 @default.
• W2905049682 hasConceptScore W2905049682C151730666 @default.
• W2905049682 hasConceptScore W2905049682C185592680 @default.
• W2905049682 hasConceptScore W2905049682C200082930 @default.
• W2905049682 hasConceptScore W2905049682C201663137 @default.
• W2905049682 hasConceptScore W2905049682C2777637488 @default.
• W2905049682 hasConceptScore W2905049682C2779343474 @default.
• W2905049682 hasConceptScore W2905049682C501593827 @default.
• W2905049682 hasConceptScore W2905049682C523546767 @default.
• W2905049682 hasConceptScore W2905049682C54355233 @default.
• W2905049682 hasConceptScore W2905049682C547475151 @default.
• W2905049682 hasConceptScore W2905049682C55493867 @default.
• W2905049682 hasConceptScore W2905049682C86803240 @default.
• W2905049682 hasConceptScore W2905049682C89423630 @default.
• W2905049682 hasConceptScore W2905049682C95444343 @default.
• W2905049682 hasLocation W29050496821 @default.
• W2905049682 hasOpenAccess W2905049682 @default.
• W2905049682 hasPrimaryLocation W29050496821 @default.
• W2905049682 hasRelatedWork W116610888 @default.
• W2905049682 hasRelatedWork W1529130961 @default.
• W2905049682 hasRelatedWork W15671914 @default.
• W2905049682 hasRelatedWork W1970803152 @default.
• W2905049682 hasRelatedWork W1983806833 @default.
• W2905049682 hasRelatedWork W2051819112 @default.
• W2905049682 hasRelatedWork W2064789887 @default.
• W2905049682 hasRelatedWork W2078876583 @default.
• W2905049682 hasRelatedWork W2096247311 @default.
• W2905049682 hasRelatedWork W2114114762 @default.
• W2905049682 hasRelatedWork W2123234828 @default.
• W2905049682 hasRelatedWork W2141064673 @default.
• W2905049682 hasRelatedWork W2170213289 @default.
• W2905049682 hasRelatedWork W2236756617 @default.
• W2905049682 hasRelatedWork W2626624015 @default.
• W2905049682 hasRelatedWork W3035221754 @default.
• W2905049682 hasRelatedWork W3040807372 @default.
• W2905049682 hasRelatedWork W3092760633 @default.
• W2905049682 hasRelatedWork W3161262588 @default.
• W2905049682 hasRelatedWork W3180468669 @default.
• W2905049682 isParatext "false" @default.
• W2905049682 isRetracted "false" @default.
• W2905049682 magId "2905049682" @default.
• W2905049682 workType "dissertation" @default.