Molecular basis for inhibition of AcrB multidrug efflux pump by novel and powerful pyranopyridine derivatives
| Autor: | Steven M. Kwasny, Timothy J. Opperman, Xiaoyuan Ding, Hanno Sjuts, Terry L. Bowlin, Alina R. Ornik, Attilio Vittorio Vargiu, Son T. Nguyen, Paolo Ruggerone, Hiroshi Nikaido, Hong-Suk Kim, Klaas M. Pos |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Models Molecular Cell division Pyridines Drug Resistance medicine.disease_cause Crystallography X-Ray Models Drug Resistance Multiple Bacterial Drug Discovery efflux pump inhibitors Crystallography Multidisciplinary Escherichia coli Proteins Bacterial Biological Sciences Anti-Bacterial Agents Infectious Diseases molecular dynamics simulation Biochemistry 5.1 Pharmaceuticals Efflux Multidrug Resistance-Associated Proteins Infection Multiple Hydrophobic and Hydrophilic Interactions Protein Structure Stereochemistry 030106 microbiology Drug design Biology Molecular Dynamics Simulation Vaccine Related 03 medical and health sciences multidrug resistance Biodefense medicine Escherichia coli Humans Antibacterial drug RND efflux transporters X-ray crystallography Pyrans Binding Sites Prevention Molecular Periplasmic space biology.organism_classification Protein Structure Tertiary Multiple drug resistance Emerging Infectious Diseases 030104 developmental biology ddc:000 X-Ray Antimicrobial Resistance Tertiary Bacteria |
| Zdroj: | Sjuts, H; Vargiu, AV; Kwasny, SM; Nguyen, ST; Kim, HS; Ding, X; et al.(2016). Molecular basis for inhibition of AcrB multidrug efflux pump by novel and powerful pyranopyridine derivatives. Proceedings of the National Academy of Sciences of the United States of America, 113(13), 3509-3514. doi: 10.1073/pnas.1602472113. UC Berkeley: Retrieved from: http://www.escholarship.org/uc/item/36v4w9g5 Proceedings of the National Academy of Sciences of the United States of America, vol 113, iss 13 Proceedings of the National Academy of Sciences of the United States of America 113(13), 3509-3514 (2016). doi:10.1073/pnas.1602472113 |
| ISSN: | 1091-6490 |
| Popis: | Proceedings of the National Academy of Sciences of the United States of America 113(13), 3509 - 3514(2016). doi:10.1073/pnas.1602472113 The Escherichia coli AcrAB-TolC efflux pump is the archetype of the resistance nodulation cell division (RND) exporters from Gram-negative bacteria. Overexpression of RND-type efflux pumps is a major factor in multidrug resistance (MDR), which makes these pumps important antibacterial drug discovery targets. We have recently developed novel pyranopyridine-based inhibitors of AcrB, which are orders of magnitude more powerful than the previously known inhibitors. However, further development of such inhibitors has been hindered by the lack of structural information for rational drug design. Although only the soluble, periplasmic part of AcrB binds and exports the ligands, the presence of the membrane-embedded domain in AcrB and its polyspecific binding behavior have made cocrystallization with drugs challenging. To overcome this obstacle, we have engineered and produced a soluble version of AcrB [AcrB periplasmic domain (AcrBper)], which is highly congruent in structure with the periplasmic part of the full-length protein, and is capable of binding substrates and potent inhibitors. Here, we describe the molecular basis for pyranopyridine-based inhibition of AcrB using a combination of cellular, X-ray crystallographic, and molecular dynamics (MD) simulations studies. The pyranopyridines bind within a phenylalanine-rich cage that branches from the deep binding pocket of AcrB, where they form extensive hydrophobic interactions. Moreover, the increasing potency of improved inhibitors correlates with the formation of a delicate protein- and water-mediated hydrogen bond network. These detailed insights provide a molecular platform for the development of novel combinational therapies using efflux pump inhibitors for combating multidrug resistant Gram-negative pathogens. Published by National Acad. of Sciences, Washington, DC |
| Databáze: | OpenAIRE |
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