{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:46:58Z","timestamp":1787028418244,"version":"build-2736575974"},"reference-count":52,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2019,8,19]],"date-time":"2019-08-19T00:00:00Z","timestamp":1566172800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The use and misuse of antibiotics has resulted in critical conditions for drug-resistant bacteria emergency, accelerating the development of antimicrobial resistance (AMR). In this context, the co-administration of an antibiotic with a compound able to restore sufficient antibacterial activity may be a successful strategy. In particular, the identification of efflux pump inhibitors (EPIs) holds promise for new antibiotic resistance breakers (ARBs). Indeed, bacterial efflux pumps have a key role in AMR development; for instance, NorA efflux pump contributes to Staphylococcus aureus (S. aureus) resistance against fluoroquinolone antibiotics (e.g., ciprofloxacin) by promoting their active extrusion from the cells. Even though NorA efflux pump is known to be a potential target for EPIs development, the absence of structural information about this protein and the little knowledge available on its mechanism of action have strongly hampered rational drug discovery efforts in this area. In the present work, we investigated at the molecular level the substrate recognition pathway of NorA through a Supervised Molecular Dynamics (SuMD) approach, using a NorA homology model. Specific amino acids were identified as playing a key role in the efflux pump-mediated extrusion of its substrate, paving the way for a deeper understanding of both the mechanisms of action and the inhibition of such efflux pumps.<\/jats:p>","DOI":"10.3390\/ijms20164041","type":"journal-article","created":{"date-parts":[[2019,8,19]],"date-time":"2019-08-19T06:10:14Z","timestamp":1566195014000},"page":"4041","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Deciphering the Molecular Recognition Mechanism of Multidrug Resistance Staphylococcus aureus NorA Efflux Pump Using a Supervised Molecular Dynamics Approach"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1687-4285","authenticated-orcid":false,"given":"Deborah","family":"Palazzotti","sequence":"first","affiliation":[{"name":"Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo 5, 35131 Padova, Italy"},{"name":"Department of Pharmaceutical Sciences, \u201cDepartment of excellence 2018-2022\u201d, University of Perugia, Via del Liceo 1, 06123 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4472-5682","authenticated-orcid":false,"given":"Maicol","family":"Bissaro","sequence":"additional","affiliation":[{"name":"Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo 5, 35131 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Bolcato","sequence":"additional","affiliation":[{"name":"Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo 5, 35131 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3337-2372","authenticated-orcid":false,"given":"Andrea","family":"Astolfi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, \u201cDepartment of excellence 2018-2022\u201d, University of Perugia, Via del Liceo 1, 06123 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9369-8564","authenticated-orcid":false,"given":"Tommaso","family":"Felicetti","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, \u201cDepartment of excellence 2018-2022\u201d, University of Perugia, Via del Liceo 1, 06123 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0971-3536","authenticated-orcid":false,"given":"Stefano","family":"Sabatini","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, \u201cDepartment of excellence 2018-2022\u201d, University of Perugia, Via del Liceo 1, 06123 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3944-0313","authenticated-orcid":false,"given":"Mattia","family":"Sturlese","sequence":"additional","affiliation":[{"name":"Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo 5, 35131 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Violetta","family":"Cecchetti","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, \u201cDepartment of excellence 2018-2022\u201d, University of Perugia, Via del Liceo 1, 06123 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3530-5042","authenticated-orcid":false,"given":"Maria Letizia","family":"Barreca","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, \u201cDepartment of excellence 2018-2022\u201d, University of Perugia, Via del Liceo 1, 06123 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7514-3802","authenticated-orcid":false,"given":"Stefano","family":"Moro","sequence":"additional","affiliation":[{"name":"Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo 5, 35131 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,8,19]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2014). 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