Analysis of AcrB in Klebsiella pneumoniae reveals natural variants promoting enhanced multidrug resistance |
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| Institution: | 1. Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, 14853, USA;2. College of Biochemical Engineering, Beijing Union University, Beijing, 100023, China;3. Department of Microbiology, Cornell University, Ithaca, NY, 14853, USA;1. Dipartimento di Scienze Chimiche, Complesso Universitario Monte Sant’Angelo, Via Cintia, 80126, Napoli, Italy;2. Istituto Nazionale Biostrutture e Biosistemi—I.N.B.B, Viale Medaglie d’Oro, 305-00136, Roma, Italy;1. Department of Biochemistry and Molecular Biology, Dalian Medical University, 9 W. Lushun South Road, Dalian 116044, China;2. College of Pharmacy, Dalian Medical University, 9 W. Lushun South Road, Dalian 116044, China;3. Department of Microbiology, Dalian Medical University, 9 W. Lushun South Road, Dalian 116044, China;5. Hospital Universitari Arnau de Vilanova, Lleida, Spain;6. Hospital Universitari Clínic, Barcelona, Spain;7. Hospital Universitario 12 de Octubre, Madrid, Spain;8. Hospital General Universitario Gregorio Marañón, Madrid, Spain;9. Hospital Universitari Joan XXIII, Tarragona, Spain;10. Hospital Universitari Mútua de Terrassa, Terrassa, Spain;11. Hospital Universitari Parc Taulí, Sabadell, Spain;12. Hospital Universitario Ramón y Cajal, Madrid, Spain;13. Hospital Universitario Reina Sofía, Córdoba, Spain;14. Hospital San Pedro de La Rioja, Logroño, Spain;15. Hospital de La Santa Creu I Sant Pau, Barcelona, Spain;p. Hospital Universitari Son Espases, Mallorca, Spain;q. Hospital Universitario Virgen Del Rocío, Sevilla, Spain;r. Hospital Universitari Vall D''Hebron, Barcelona, Spain;1. Department of Microbiology, Hospital Universitari de Bellvitge, Institut D’Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain;2. Research Network for Respiratory Diseases (CIBERES), ISCIII, Madrid, Spain;3. Research Network for Infectious Diseases (CIBERINFEC), ISCIII, Madrid, Spain;4. Department of Pathology and Experimental Therapeutics, College of Medicine, Universitat de Barcelona, Barcelona, Spain;1. Department of Food Science & Technology, 2 Science Drive 2, Faculty of Science, National University of Singapore, Singapore, 117543;2. Department of Biological Sciences, 14 Science Drive 4, Faculty of Science, National University of Singapore, Singapore, 117543;3. Centre for Advanced Microscopy, The Australian National University, 131 Garran Road, Acton, ACT 2601, Australia |
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| Abstract: | Infections caused by Klebsiella pneumoniae are often difficult to manage due to the high frequency of multidrug resistance, often conferred by efflux pumps. In this study, we analyzed sequence variations of the major RND family multidrug efflux pump AcrB from 387 assembled K. pneumoniae genomes. We confirm that AcrB is a highly-conserved efflux pump in K. pneumoniae, and identified several variants that were prevalent in clinical isolates. Molecular dynamics analyses on two of these variants (L118M and S966A) suggested conformational changes that may correlate with increased drug efflux capabilities. The L118M change resulted in enhanced protein rigidity while the flexibility of drug binding pockets was stable or increased, and the interactions between the proximal pockets and water molecules were stronger. For S966A, the significantly enlarged proximal pocket suggested higher drug accommodation ability. Consistent with these predictions, the L118M and S966A variants conferred a slightly increased ability to grow in the presence of tetracycline and to survive cefoxitin exposure when overexpressed. In summary, our results suggest that the emergence of enhanced-function AcrB variants may be a potential risk for increased antibiotic resistance in clinical K. pneumoniae isolates. |
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| Keywords: | AcrAB Efflux pump Resistance-nodulation-cell division Antibiotic resistance |
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