Unraveling the ligand specificity and promiscuity of the Staphylococcus aureus NorA efflux pump: a computational study

References

• Abraham, M. J., Murtola, T., Schulz, R., Páll, S., Smith, J. C., Hess, B., & Lindah, E. (2015). GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX, 1-2, 19–25. https://doi.org/10.1016/j.softx.2015.06.001
   Google Scholar
• Alegre, K. O., Paul, S., Labarbuta, P., & Law, C. J. (2016). Insight into determinants of substrate binding and transport in a multidrug efflux protein. Scientific Reports, 2016 6:16(1), 22833. https://doi.org/10.1038/srep22833
   PubMedGoogle Scholar
• Astolfi, A., Felicetti, T., Iraci, N., Manfroni, G., Massari, S., Pietrella, D., Tabarrini, O., Kaatz, G. W., Barreca, M. L., Sabatini, S., & Cecchetti, V. (2017). Pharmacophore-based repositioning of approved drugs as novel Staphylococcus aureus NorA efflux pump inhibitors. Journal of Medicinal Chemistry, 60(4), 1598–1604. https://doi.org/10.1021/acs.jmedchem.6b01439
   PubMed Web of Science ®Google Scholar
• Bharadwaj, A., Rastogi, A., Pandey, S., Gupta, S., & Sohal, J. S. (2022). Multidrug-resistant bacteria: Their mechanism of action and prophylaxis. BioMed Research International, 2022, 5419874–5419817.). https://doi.org/10.1155/2022/5419874
   PubMed Web of Science ®Google Scholar
• Bhaskar, B. V., Chandra Babu, T. M., Reddy, N. V., & Rajendra, W. (2016). Homology modeling, molecular dynamics, and virtual screening of nora efflux pump inhibitors of Staphylococcus aureus. Drug Design, Development and Therapy, 10, 3237–3252. https://doi.org/10.2147/DDDT.S113556
   PubMed Web of Science ®Google Scholar
• Brawley, D. N., Sauer, D. B., Li, J., Zheng, X., Koide, A., Jedhe, G. S., Suwatthee, T., Song, J., Liu, Z., Arora, P. S., Koide, S., Torres, V. J., Wang, D. N., & Traaseth, N. J. (2022). Structural basis for inhibition of the drug efflux pump NorA from Staphylococcus aureus. Nature Chemical Biology, 18(7), 706–712. https://doi.org/10.1038/S41589-022-00994-9
   PubMed Web of Science ®Google Scholar
• Brincat, J. P., Carosati, E., Sabatini, S., Manfroni, G., Fravolini, A., Raygada, J. L., Patel, D., Kaatz, G. W., & Cruciani, G. (2011). Discovery of novel inhibitors of the NorA multidrug transporter of staphylococcus aureus. Journal of Medicinal Chemistry, 54(1), 354–365. https://doi.org/10.1021/JM1011963/SUPPL_FILE/JM1011963_SI_001.PDF
   PubMed Web of Science ®Google Scholar
• Buonerba, F., Lepri, S., Goracci, L., Schindler, B. D., Seo, S. M., Kaatz, G. W., & Cruciani, G. (2017). Improved potency of indole-based NorA efflux pump inhibitors: from serendipity toward rational design and development. Journal of Medicinal Chemistry, 60(1), 517–523. https://doi.org/10.1021/ACS.JMEDCHEM.6B01281/SUPPL_FILE/JM6B01281_SI_002.CSV
   PubMed Web of Science ®Google Scholar
• Costa, L. M., de Macedo, E. V., Oliveira, F. A. A., Ferreira, J. H. L., Gutierrez, S. J. C., Peláez, W. J., Lima, F. C. A., de Siqueira Júnior, J. P., Coutinho, H. D. M., Kaatz, G. W., de Freitas, R. M., & Barreto, H. M. (2016). Inhibition of the NorA efflux pump of Staphylococcus aureus by synthetic riparins. Journal of Applied Microbiology, 121(5), 1312–1322. https://doi.org/10.1111/JAM.13258
   PubMed Web of Science ®Google Scholar
• Darby, E. M., Trampari, E., Siasat, P., Gaya, M. S., Alav, I., Webber, M. A., & Blair, J. M. A. (2023). Molecular mechanisms of antibiotic resistance revisited. Nature Reviews Microbiology, 21(5), 280–295. (https://doi.org/10.1038/s41579-022-00820-y
   PubMed Web of Science ®Google Scholar
• Davies, M., Nowotka, M., Papadatos, G., Dedman, N., Gaulton, A., Atkinson, F., Bellis, L., & Overington, J. P. (2015). ChEMBL web services: Streamlining access to drug discovery data and utilities. Nucleic Acids Research, 43(W1), W612–W620. https://doi.org/10.1093/nar/gkv352
   PubMed Web of Science ®Google Scholar
• De Oliveira, D. M. P., Forde, B. M., Kidd, T. J., Harris, P. N. A., Schembri, M. A., Beatson, S. A., Paterson, D. L., & Walker, M. J. (2020). Antimicrobial resistance in ESKAPE pathogens. Clinical Microbiology Reviews, 33(3) https://doi.org/10.1128/CMR.00181-19
   PubMed Web of Science ®Google Scholar
• DeMarco, C. E., Cushing, L. A., Frempong-Manso, E., Seo, S. M., Jaravaza, T. A. A., & Kaatz, G. W. (2007). Efflux-related resistance to norfloxacin, dyes, and biocides in bloodstream isolates of Staphylococcus aureus. Antimicrobial Agents and Chemotherapy, 51(9), 3235–3239. https://doi.org/10.1128/AAC.00430-07
   PubMed Web of Science ®Google Scholar
• Drew, D., North, R. A., Nagarathinam, K., & Tanabe, M. (2021). Structures and general transport mechanisms by the major facilitator Superfamily (MFS). Chemical Reviews, 121(9), 5289–5335. https://doi.org/10.1021/ACS.CHEMREV.0C00983/ASSET/IMAGES/LARGE/CR0C00983_0019.JPEG
   PubMed Web of Science ®Google Scholar
• Ester, M., Kriegel, H.-P., Sander, J., & Xu, X. (1996). A Density-Based Algorithm for Discovering Clusters in Large Spatial Databases with Noise. Proceedings of the 2nd International Conference on Knowledge Discovery and Data Mining.
   Google Scholar
• Felicetti, T., Cannalire, R., Nizi, M. G., Tabarrini, O., Massari, S., Barreca, M. L., Manfroni, G., Schindler, B. D., Cecchetti, V., Kaatz, G. W., & Sabatini, S. (2018). Studies on 2-phenylquinoline Staphylococcus aureus NorA efflux pump inhibitors: New insights on the C-6 position. European Journal of Medicinal Chemistry, 155, 428–433. https://doi.org/10.1016/j.ejmech.2018.06.013
   PubMed Web of Science ®Google Scholar
• Felicetti, T., Cannalire, R., Pietrella, D., Latacz, G., Lubelska, A., Manfroni, G., Barreca, M. L., Massari, S., Tabarrini, O., Kieć-Kononowicz, K., Schindler, B. D., Kaatz, G. W., Cecchetti, V., & Sabatini, S. (2018). 2-Phenylquinoline S. aureus NorA Efflux Pump Inhibitors: Evaluation of the Importance of Methoxy Group Introduction. Journal of Medicinal Chemistry, 61(17), 7827–7848. https://doi.org/10.1021/acs.jmedchem.8b00791
   PubMed Web of Science ®Google Scholar
• Ferreira, C., Abrantes, P., Costa, S. S., Viveiros, M., & Couto, I. (2022). Occurrence and variability of the efflux pump gene norA across the Staphylococcus Genus †. International Journal of Molecular Sciences, 23(23), 15306. https://doi.org/10.3390/ijms232315306
   PubMed Web of Science ®Google Scholar
• Gaurav, A., Bakht, P., Saini, M., Pandey, S., & Pathania, R. (2023). Role of bacterial efflux pumps in antibiotic resistance, virulence, and strategies to discover novel efflux pump inhibitors. Microbiology (Reading, England), 169 (5). (https://doi.org/10.1099/mic.0.001333
   PubMed Web of Science ®Google Scholar
• German, N., Wei, P., Kaatz, G. W., & Kerns, R. J. (2008). Synthesis and evaluation of fluoroquinolone derivatives as substrate-based inhibitors of bacterial efflux pumps. European Journal of Medicinal Chemistry, 43(11), 2453–2463. https://doi.org/10.1016/j.ejmech.2008.01.042
   PubMed Web of Science ®Google Scholar
• Huang, J., & Mackerell, A. D. (2013). CHARMM36 all-atom additive protein force field: Validation based on comparison to NMR data. Journal of Computational Chemistry, 34(25), 2135–2145. https://doi.org/10.1002/JCC.23354
   PubMed Web of Science ®Google Scholar
• Jo, S., Kim, T., Iyer, V. G., & Im, W. (2008). CHARMM-GUI: A web-based graphical user interface for CHARMM. Journal of Computational Chemistry, 29(11), 1859–1865. https://doi.org/10.1002/JCC.20945
   PubMed Web of Science ®Google Scholar
• Kaatz, G. W., Moudgal, V. V., Seo, S. M., Hansen, J. B., & Kristiansen, J. E. (2003). Phenylpiperidine selective serotonin reuptake inhibitors interfere with multidrug efflux pump activity in Staphylococcus aureus. International Journal of Antimicrobial Agents, 22(3), 254–261. https://doi.org/10.1016/S0924-8579(03)00220-6
   PubMed Web of Science ®Google Scholar
• Kaatz, G. W., Seo, S. M., & Ruble, C. A. (1993). Efflux-mediated fluoroquinolone resistance in Staphylococcus aureus. Antimicrobial Agents and Chemotherapy, 37(5), 1086–1094. https://doi.org/10.1128/AAC.37.5.1086
   PubMed Web of Science ®Google Scholar
• Koes, D. R., Baumgartner, M. P., & Camacho, C. J. (2013). Lessons learned in empirical scoring with smina from the CSAR 2011 benchmarking exercise. Journal of Chemical Information and Modeling, 53(8), 1893–1904. https://doi.org/10.1021/ci300604z
   PubMed Web of Science ®Google Scholar
• Lamut, A., Peterlin Mašič, L., Kikelj, D., & Tomašič, T. (2019). Efflux pump inhibitors of clinically relevant multidrug resistant bacteria. Medicinal Research Reviews, 39(6), 2460–2504. (https://doi.org/10.1002/med.21591
   PubMed Web of Science ®Google Scholar
• Lepri, S., Buonerba, F., Goracci, L., Velilla, I., Ruzziconi, R., Schindler, B. D., Seo, S. M., Kaatz, G. W., & Cruciani, G. (2016). Indole based weapons to fight antibiotic resistance: A structure-activity relationship study. Journal of Medicinal Chemistry, 59(3), 867–891. https://doi.org/10.1021/ACS.JMEDCHEM.5B01219/SUPPL_FILE/JM5B01219_SI_001.CSV
   PubMed Web of Science ®Google Scholar
• Lewis, K., & Klibanov, A. M. (2005). Surpassing nature: Rational design of sterile-surface materials. Trends in Biotechnology, 23(7), 343–348. https://doi.org/10.1016/j.tibtech.2005.05.004
   PubMed Web of Science ®Google Scholar
• Lomize, M. A., Pogozheva, I. D., Joo, H., Mosberg, H. I., & Lomize, A. L. (2012). OPM database and PPM web server: Resources for positioning of proteins in membranes. Nucleic Acids Research, 40(Database issue), D370–D376. https://doi.org/10.1093/nar/gkr703
   PubMed Web of Science ®Google Scholar
• McGuinness, W. A., Malachowa, N., & DeLeo, F. R. (2017). Vancomycin resistance in Staphylococcus aureus. Yale Journal of Biology and Medicine, 90(2). https://doi.org/10.1201/9780849340574-15
   PubMed Web of Science ®Google Scholar
• Mendez, D., Gaulton, A., Bento, A. P., Chambers, J., De Veij, M., Félix, E., Magariños, M. P., Mosquera, J. F., Mutowo, P., Nowotka, M., Gordillo-Marañón, M., Hunter, F., Junco, L., Mugumbate, G., Rodriguez-Lopez, M., Atkinson, F., Bosc, N., Radoux, C. J., Segura-Cabrera, A., Hersey, A., & Leach, A. R. (2019). ChEMBL: Towards direct deposition of bioassay data. Nucleic Acids Research, 47(D1), D930–D940. https://doi.org/10.1093/NAR/GKY1075
   PubMed Web of Science ®Google Scholar
• Monteiro, K. L. C., de Aquino, T. M., & Mendonça Junior, F. J. B. (2020). An update on Staphylococcus aureus NorA efflux pump inhibitors. Current Topics in Medicinal Chemistry, 20(24), 2168–2185. https://doi.org/10.2174/1568026620666200704135837
   PubMed Web of Science ®Google Scholar
• Neyfakh, A. A., Borsch, C. M., & Kaatz, G. W. (1993). Fluoroquinolone resistance protein NorA of Staphylococcus aureus is a multidrug efflux transporter. Antimicrobial Agents and Chemotherapy, 37(1), 128–129. (https://doi.org/10.1128/AAC.37.1.128
   PubMed Web of Science ®Google Scholar
• Noguchi, N., Okada, H., Narui, K., & Sasatsu, M. (2004). Comparison of the nucleotide sequence and expression of norA genes and microbial susceptibility in 21 strains of Staphylococcus aureus. Microbial Drug Resistance (Larchmont, N.Y.), 10(3), 197–203. https://doi.org/10.1089/MDR.2004.10.197
   PubMed Web of Science ®Google Scholar
• O’Boyle, N. M., Banck, M., James, C. A., Morley, C., Vandermeersch, T., & Hutchison, G. R. (2011). Open babel: An open chemical toolbox. Journal of Cheminformatics, 3(10), 33. https://doi.org/10.1186/1758-2946-3-33/TABLES/2
   PubMed Web of Science ®Google Scholar
• Palazzotti, D., Bissaro, M., Bolcato, G., Astolfi, A., Felicetti, T., Sabatini, S., Sturlese, M., Cecchetti, V., Barreca, M. L., & Moro, S. (2019). Deciphering the molecular recognition mechanism of multidrug resistance Staphylococcus aureus NorA Efflux pump using a supervised molecular dynamics approach. International Journal of Molecular Sciences, 20(16), 4041. https://doi.org/10.3390/IJMS20164041
   PubMed Web of Science ®Google Scholar
• Palazzotti, D., Felicetti, T., Sabatini, S., Moro, S., Letizia Barreca, M., Sturlese, M., & Astolfi, A. (2023). Fighting antimicrobial resistance: Insights on how the Staphylococcus aureus NorA efflux pump recognizes 2-phenylquinoline inhibitors by supervised molecular dynamics (SuMD) and molecular docking simulations. Journal of Chemical Information and Modeling, 63(15), 4875–4887. https://doi.org/10.1021/acs.jcim.3c00516
   PubMed Web of Science ®Google Scholar
• Papkou, A., Hedge, J., Kapel, N., Young, B., & MacLean, R. C. (2020). Efflux pump activity potentiates the evolution of antibiotic resistance across S. aureus isolates. Nature Communications, 11(1) https://doi.org/10.1038/s41467-020-17735-y
   PubMed Web of Science ®Google Scholar
• Pedregosa, F., Varoquaux, G., Gramfort, A., Michel, V., Thirion, B., Grisel, O., Blondel, M., Prettenhofer, P., Weiss, R., Dubourg, V., Vanderplas, J., Passos, A., Cournapeau, D., Brucher, M., Perrot, M., & Duchesnay, É. (2011). Scikit-learn: Machine learning in python. Journal of Machine Learning Research, 12, 2825–2830.
   Web of Science ®Google Scholar
• Pieroni, M., Sabatini, S., Massari, S., Kaatz, G. W., Cecchetti, V., & Tabarrini, O. (2012). Searching for innovative quinolone-like scaffolds: Synthesis and biological evaluation of 2,1-benzothiazine 2,2-dioxide derivatives. MedChemComm, 3(9), 1092–1097. https://doi.org/10.1039/c2md20101a
   Web of Science ®Google Scholar
• Prestinaci, F., Pezzotti, P., & Pantosti, A. (2015). Antimicrobial resistance: A global multifaceted phenomenon. Pathogens and Global Health, 109(7), 309–318. https://doi.org/10.1179/2047773215Y.0000000030
   PubMed Web of Science ®Google Scholar
• Quistgaard, E. M., Löw, C., Guettou, F., & Nordlund, P. (2016). Understanding transport by the major facilitator superfamily (MFS): structures pave the way. Nature Reviews. Molecular Cell Biology, 17(2), 123–132. https://doi.org/10.1038/NRM.2015.25
   PubMed Web of Science ®Google Scholar
• Redhu, A. K., Banerjee, A., Shah, A. H., Moreno, A., Rawal, M. K., Nair, R., Falson, P., & Prasad, R. (2018). Molecular basis of substrate polyspecificity of the Candida albicans Mdr1p Multidrug/H + Antiporter. Journal of Molecular Biology, 430(5), 682–694. https://doi.org/10.1016/J.JMB.2018.01.005
   PubMed Web of Science ®Google Scholar
• Sabatini, S., Gosetto, F., Iraci, N., Barreca, M. L., Massari, S., Sancineto, L., Manfroni, G., Tabarrini, O., Dimovska, M., Kaatz, G. W., & Cecchetti, V. (2013). Re-evolution of the 2-phenylquinolines: Ligand-based design, synthesis, and biological evaluation of a potent new class of staphylococcus aureus NorA efflux pump inhibitors to combat antimicrobial resistance. Journal of Medicinal Chemistry, 56(12), 4975–4989. https://doi.org/10.1021/jm400262a
   PubMed Web of Science ®Google Scholar
• Sabatini, S., Gosetto, F., Manfroni, G., Tabarrini, O., Kaatz, G. W., Patel, D., & Cecchetti, V. (2011). Evolution from a natural flavones nucleus to obtain 2-(4-Propoxyphenyl)quinoline derivatives as potent inhibitors of the S. aureus NorA efflux pump. Journal of Medicinal Chemistry, 54(16), 5722–5736. https://doi.org/10.1021/JM200370Y
   PubMed Web of Science ®Google Scholar
• Sabatini, S., Gosetto, F., Serritella, S., Manfroni, G., Tabarrini, O., Iraci, N., Brincat, J. P., Carosati, E., Villarini, M., Kaatz, G. W., & Cecchetti, V. (2012). Pyrazolo[4,3-c] [1,2]benzothiazines 5,5-dioxide: A promising new class of staphylococcus aureus NorA efflux pump inhibitors. Journal of Medicinal Chemistry, 55(7), 3568–3572. https://doi.org/10.1021/jm201446h
   PubMed Web of Science ®Google Scholar
• Sabatini, S., Kaatz, G. W., Rossolini, G. M., Brandini, D., & Fravolini, A. (2008). From phenothiazine to 3-phenyl-1,4-benzothiazine derivatives as inhibitors of the Staphylococcus aureus NorA multidrug efflux pump. Journal of Medicinal Chemistry, 51(14), 4321–4330. https://doi.org/10.1021/jm701623q
   PubMed Web of Science ®Google Scholar
• Salentin, S., Schreiber, S., Haupt, V. J., Adasme, M. F., & Schroeder, M. (2015). PLIP: Fully automated protein-ligand interaction profiler. Nucleic Acids Research, 43(W1), W443–W447. https://doi.org/10.1093/NAR/GKV315
   PubMed Web of Science ®Google Scholar
• Sangwan, P. L., Koul, J. L., Koul, S., Reddy, M. V., Thota, N., Khan, I. A., Kumar, A., Kalia, N. P., & Qazi, G. N. (2008). Piperine analogs as potent Staphylococcus aureus NorA efflux pump inhibitors. Bioorganic & Medicinal Chemistry, 16(22), 9847–9857. https://doi.org/10.1016/j.bmc.2008.09.042
   PubMed Web of Science ®Google Scholar
• Shang, Y., Lv, P., Su, D., Li, Y., Liang, Y., Ma, C., & Yang, C. (2022). Evolutionary conservative analysis revealed novel functional sites in the efflux pump NorA of Staphylococcus aureus. The Journal of Antimicrobial Chemotherapy, 77(3), 675–681. https://doi.org/10.1093/JAC/DKAB453
   PubMed Web of Science ®Google Scholar
• Thai, K.-M., Ngo, T.-D., Phan, T.-V., Tran, T.-D., Nguyen, N.-V., Nguyen, T.-H., & Le, M.-T. (2015). Virtual screening for novel Staphylococcus Aureus NorA efflux pump inhibitors from natural products. Medicinal Chemistry (Shariqah (United Arab Emirates)), 11(2), 135–155. https://doi.org/10.2174/1573406410666140902110903
   PubMed Web of Science ®Google Scholar
• Urban-Chmiel, R., Marek, A., Stępień-Pyśniak, D., Wieczorek, K., Dec, M., Nowaczek, A., & Osek, J. (2022). Antibiotic resistance in bacteria: A review. Antibiotics, 11(8), 1079. (https://doi.org/10.3390/antibiotics11081079
   Google Scholar
• Valdés-Tresanco, M. S., Valdés-Tresanco, M. E., Valiente, P. A., & Moreno, E. (2021). Gmx_MMPBSA: A new tool to perform end-state free energy calculations with GROMACS. Journal of Chemical Theory and Computation, 17(10), 6281–6291. https://doi.org/10.1021/acs.jctc.1c00645
   PubMed Web of Science ®Google Scholar
• Vanommeslaeghe, K., Hatcher, E., Acharya, C., Kundu, S., Zhong, S., Shim, J., Darian, E., Guvench, O., Lopes, P., Vorobyov, I., & Mackerell, A. D. (2010). CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields. Journal of Computational Chemistry, 31(4), 671–690. https://doi.org/10.1002/jcc.21367
   PubMed Web of Science ®Google Scholar
• Varadi, M., Anyango, S., Deshpande, M., Nair, S., Natassia, C., Yordanova, G., Yuan, D., Stroe, O., Wood, G., Laydon, A., Žídek, A., Green, T., Tunyasuvunakool, K., Petersen, S., Jumper, J., Clancy, E., Green, R., Vora, A., Lutfi, M., … Velankar, S. (2022). AlphaFold protein structure database: Massively expanding the structural coverage of protein-sequence space with high-accuracy models. Nucleic Acids Research, 50(D1), D439–D444. https://doi.org/10.1093/nar/gkab1061
   PubMed Web of Science ®Google Scholar
• Vidaillac, C., Guillon, J., Arpin, C., Forfar-Bares, I., Ba, B. B., Grellet, J., Moreau, S., Caignard, D. H., Jarry, C., & Quentin, C. (2007). Synthesis of omeprazole analogues and evaluation of these as potential inhibitors of the multidrug efflux pump NorA of Staphylococcus aureus. Antimicrobial Agents and Chemotherapy, 51(3), 831–838. https://doi.org/10.1128/AAC.01306-05
   PubMed Web of Science ®Google Scholar
• Volkamer, A., Kuhn, D., Rippmann, F., & Rarey, M. (2012). DoGSiteScorer: A web server for automatic binding site prediction, analysis and druggability assessment. Bioinformatics (Oxford, England), 28(15), 2074–2075. https://doi.org/10.1093/BIOINFORMATICS/BTS310
   PubMed Web of Science ®Google Scholar
• Vouga, M., & Greub, G. (2016). Emerging bacterial pathogens: The past and beyond. Clinical Microbiology and Infection: The Official Publication of the European Society of Clinical Microbiology and Infectious Diseases, 22(1), 12–21. https://doi.org/10.1016/J.CMI.2015.10.010
   PubMed Web of Science ®Google Scholar
• Zhang, S., Krieger, J. M., Zhang, Y., Kaya, C., Kaynak, B., Mikulska-Ruminska, K., Doruker, P., Li, H., & Bahar, I. (2021). ProDy 2.0: Increased scale and scope after 10 years of protein dynamics modelling with Python. Bioinformatics (Oxford, England), 37(20), 3657–3659. https://doi.org/10.1093/bioinformatics/btab187
   PubMed Web of Science ®Google Scholar