Deciphering the Molecular Recognition Mechanism of Multidrug Resistance <i>Staphylococcus aureus</i> NorA Efflux Pump Using a Supervised Molecular Dynamics Approach

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 b...

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Main Authors: Deborah Palazzotti, Maicol Bissaro, Giovanni Bolcato, Andrea Astolfi, Tommaso Felicetti, Stefano Sabatini, Mattia Sturlese, Violetta Cecchetti, Maria Letizia Barreca, Stefano Moro
Format: Article
Language:English
Published: MDPI AG 2019-08-01
Series:International Journal of Molecular Sciences
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Online Access:https://www.mdpi.com/1422-0067/20/16/4041
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spelling doaj-d7a80105812947bea0c5584c51055b5a2020-11-25T00:28:00ZengMDPI AGInternational Journal of Molecular Sciences1422-00672019-08-012016404110.3390/ijms20164041ijms20164041Deciphering the Molecular Recognition Mechanism of Multidrug Resistance <i>Staphylococcus aureus</i> NorA Efflux Pump Using a Supervised Molecular Dynamics ApproachDeborah Palazzotti0Maicol Bissaro1Giovanni Bolcato2Andrea Astolfi3Tommaso Felicetti4Stefano Sabatini5Mattia Sturlese6Violetta Cecchetti7Maria Letizia Barreca8Stefano Moro9Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo 5, 35131 Padova, ItalyMolecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo 5, 35131 Padova, ItalyMolecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo 5, 35131 Padova, ItalyDepartment of Pharmaceutical Sciences, “Department of excellence 2018-2022”, University of Perugia, Via del Liceo 1, 06123 Perugia, ItalyDepartment of Pharmaceutical Sciences, “Department of excellence 2018-2022”, University of Perugia, Via del Liceo 1, 06123 Perugia, ItalyDepartment of Pharmaceutical Sciences, “Department of excellence 2018-2022”, University of Perugia, Via del Liceo 1, 06123 Perugia, ItalyMolecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo 5, 35131 Padova, ItalyDepartment of Pharmaceutical Sciences, “Department of excellence 2018-2022”, University of Perugia, Via del Liceo 1, 06123 Perugia, ItalyDepartment of Pharmaceutical Sciences, “Department of excellence 2018-2022”, University of Perugia, Via del Liceo 1, 06123 Perugia, ItalyMolecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo 5, 35131 Padova, ItalyThe 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 <i>Staphylococcus aureus</i> (<i>S. aureus</i>) 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.https://www.mdpi.com/1422-0067/20/16/4041antimicrobial resistancenorA efflux pumphomology modelingmolecular dynamics simulationsupervised molecular dynamics
collection DOAJ
language English
format Article
sources DOAJ
author Deborah Palazzotti
Maicol Bissaro
Giovanni Bolcato
Andrea Astolfi
Tommaso Felicetti
Stefano Sabatini
Mattia Sturlese
Violetta Cecchetti
Maria Letizia Barreca
Stefano Moro
spellingShingle Deborah Palazzotti
Maicol Bissaro
Giovanni Bolcato
Andrea Astolfi
Tommaso Felicetti
Stefano Sabatini
Mattia Sturlese
Violetta Cecchetti
Maria Letizia Barreca
Stefano Moro
Deciphering the Molecular Recognition Mechanism of Multidrug Resistance <i>Staphylococcus aureus</i> NorA Efflux Pump Using a Supervised Molecular Dynamics Approach
International Journal of Molecular Sciences
antimicrobial resistance
norA efflux pump
homology modeling
molecular dynamics simulation
supervised molecular dynamics
author_facet Deborah Palazzotti
Maicol Bissaro
Giovanni Bolcato
Andrea Astolfi
Tommaso Felicetti
Stefano Sabatini
Mattia Sturlese
Violetta Cecchetti
Maria Letizia Barreca
Stefano Moro
author_sort Deborah Palazzotti
title Deciphering the Molecular Recognition Mechanism of Multidrug Resistance <i>Staphylococcus aureus</i> NorA Efflux Pump Using a Supervised Molecular Dynamics Approach
title_short Deciphering the Molecular Recognition Mechanism of Multidrug Resistance <i>Staphylococcus aureus</i> NorA Efflux Pump Using a Supervised Molecular Dynamics Approach
title_full Deciphering the Molecular Recognition Mechanism of Multidrug Resistance <i>Staphylococcus aureus</i> NorA Efflux Pump Using a Supervised Molecular Dynamics Approach
title_fullStr Deciphering the Molecular Recognition Mechanism of Multidrug Resistance <i>Staphylococcus aureus</i> NorA Efflux Pump Using a Supervised Molecular Dynamics Approach
title_full_unstemmed Deciphering the Molecular Recognition Mechanism of Multidrug Resistance <i>Staphylococcus aureus</i> NorA Efflux Pump Using a Supervised Molecular Dynamics Approach
title_sort deciphering the molecular recognition mechanism of multidrug resistance <i>staphylococcus aureus</i> nora efflux pump using a supervised molecular dynamics approach
publisher MDPI AG
series International Journal of Molecular Sciences
issn 1422-0067
publishDate 2019-08-01
description 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 <i>Staphylococcus aureus</i> (<i>S. aureus</i>) 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.
topic antimicrobial resistance
norA efflux pump
homology modeling
molecular dynamics simulation
supervised molecular dynamics
url https://www.mdpi.com/1422-0067/20/16/4041
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