Common recognition topology of mex transporters of Pseudomonas aeruginosa revealed by molecular modelling
The secondary transporters of the resistance-nodulation-cell division (RND) superfamily mediate multidrug resistance in Gram-negative bacteria like Pseudomonas aeruginosa. Among these RND transporters, MexB, MexF, and MexY, with partly overlapping specificities, have been implicated in pathogenicity...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-11-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.1021916/full |
| _version_ | 1798019042572763136 |
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| author | Andrea Catte Venkata K. Ramaswamy Attilio Vittorio Vargiu Giuliano Malloci Andrea Bosin Paolo Ruggerone |
| author_facet | Andrea Catte Venkata K. Ramaswamy Attilio Vittorio Vargiu Giuliano Malloci Andrea Bosin Paolo Ruggerone |
| author_sort | Andrea Catte |
| collection | DOAJ |
| description | The secondary transporters of the resistance-nodulation-cell division (RND) superfamily mediate multidrug resistance in Gram-negative bacteria like Pseudomonas aeruginosa. Among these RND transporters, MexB, MexF, and MexY, with partly overlapping specificities, have been implicated in pathogenicity. Only the structure of the former has been resolved experimentally, which together with the lack of data about the functional dynamics of the full set of transporters, limited a systematic investigation of the molecular determinants defining their peculiar and shared features. In a previous work (Ramaswamy et al., Front. Microbiol., 2018, 9, 1144), we compared at an atomistic level the two main putative recognition sites (named access and deep binding pockets) of MexB and MexY. In this work, we expand the comparison by performing extended molecular dynamics (MD) simulations of these transporters and the pathologically relevant transporter MexF. We employed a more realistic model of the inner phospholipid membrane of P. aeruginosa and more accurate force-fields. To elucidate structure/dynamics-activity relationships we performed physico-chemical analyses and mapped the binding propensities of several organic probes on all transporters. Our data revealed the presence, also in MexF, of a few multifunctional sites at locations equivalent to the access and deep binding pockets detected in MexB. Furthermore, we report for the first time about the multidrug binding abilities of two out of five gates of the channels deputed to peripheral (early) recognition of substrates. Overall, our findings help to define a common “recognition topology” characterizing Mex transporters, which can be exploited to optimize transport and inhibition propensities of antimicrobial compounds. |
| first_indexed | 2024-04-11T16:34:17Z |
| format | Article |
| id | doaj.art-ea91245656ee42d0b21f894ae381c12b |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-11T16:34:17Z |
| publishDate | 2022-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-ea91245656ee42d0b21f894ae381c12b2022-12-22T04:13:54ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-11-011310.3389/fphar.2022.10219161021916Common recognition topology of mex transporters of Pseudomonas aeruginosa revealed by molecular modellingAndrea CatteVenkata K. RamaswamyAttilio Vittorio VargiuGiuliano MallociAndrea BosinPaolo RuggeroneThe secondary transporters of the resistance-nodulation-cell division (RND) superfamily mediate multidrug resistance in Gram-negative bacteria like Pseudomonas aeruginosa. Among these RND transporters, MexB, MexF, and MexY, with partly overlapping specificities, have been implicated in pathogenicity. Only the structure of the former has been resolved experimentally, which together with the lack of data about the functional dynamics of the full set of transporters, limited a systematic investigation of the molecular determinants defining their peculiar and shared features. In a previous work (Ramaswamy et al., Front. Microbiol., 2018, 9, 1144), we compared at an atomistic level the two main putative recognition sites (named access and deep binding pockets) of MexB and MexY. In this work, we expand the comparison by performing extended molecular dynamics (MD) simulations of these transporters and the pathologically relevant transporter MexF. We employed a more realistic model of the inner phospholipid membrane of P. aeruginosa and more accurate force-fields. To elucidate structure/dynamics-activity relationships we performed physico-chemical analyses and mapped the binding propensities of several organic probes on all transporters. Our data revealed the presence, also in MexF, of a few multifunctional sites at locations equivalent to the access and deep binding pockets detected in MexB. Furthermore, we report for the first time about the multidrug binding abilities of two out of five gates of the channels deputed to peripheral (early) recognition of substrates. Overall, our findings help to define a common “recognition topology” characterizing Mex transporters, which can be exploited to optimize transport and inhibition propensities of antimicrobial compounds.https://www.frontiersin.org/articles/10.3389/fphar.2022.1021916/fullRND efflux pumpsmultidrug transporterPseudomonas aeruginosaantibiotic resistancemolecular dynamicsmolecular modeling |
| spellingShingle | Andrea Catte Venkata K. Ramaswamy Attilio Vittorio Vargiu Giuliano Malloci Andrea Bosin Paolo Ruggerone Common recognition topology of mex transporters of Pseudomonas aeruginosa revealed by molecular modelling Frontiers in Pharmacology RND efflux pumps multidrug transporter Pseudomonas aeruginosa antibiotic resistance molecular dynamics molecular modeling |
| title | Common recognition topology of mex transporters of Pseudomonas aeruginosa revealed by molecular modelling |
| title_full | Common recognition topology of mex transporters of Pseudomonas aeruginosa revealed by molecular modelling |
| title_fullStr | Common recognition topology of mex transporters of Pseudomonas aeruginosa revealed by molecular modelling |
| title_full_unstemmed | Common recognition topology of mex transporters of Pseudomonas aeruginosa revealed by molecular modelling |
| title_short | Common recognition topology of mex transporters of Pseudomonas aeruginosa revealed by molecular modelling |
| title_sort | common recognition topology of mex transporters of pseudomonas aeruginosa revealed by molecular modelling |
| topic | RND efflux pumps multidrug transporter Pseudomonas aeruginosa antibiotic resistance molecular dynamics molecular modeling |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.1021916/full |
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