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

Volumn 113, Issue 13, 2016, Pages 3509-3514

  Sjuts, Hanno ^a   Vargiu, Attilio V ^b   Kwasny, Steven M ^c   Nguyen, Son T ^c   Kim, Hong Suk ^d   Ding, Xiaoyuan ^c   Ornik, Alina R ^a   Ruggerone, Paolo ^b   Bowlin, Terry L ^c   Nikaido, Hiroshi ^d   Pos, Klaas M ^a   Opperman, Timothy J ^c  

^a GOETHE UNIVERSITY   (Germany)

^b UNIVERSITY OF CAGLIARI   (Italy)

^c MICROBIOTIX INC   (United States)

^d UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

Efflux pump inhibitors; Molecular dynamics simulation; Multidrug resistance; RND efflux transporters; X ray crystallography

Indexed keywords

ACETAMIDE; ACRB MULTIDRUG EFFLUX PUMP; ACRYLAMIDE; ANTIBIOTIC AGENT; EFFLUX PUMP INHIBITOR; ESCHERICHIA COLI PROTEIN; HOE 33342; LEVOFLOXACIN; MBX 2319; MBX 2913; MBX 2931; MBX 3132; MBX 3135; MINOCYCLINE; PHENYL GROUP; PHENYLALANINE; PYRIDINE DERIVATIVE; RHODAMINE 6G; THREONINE; TRYPTOPHAN DERIVATIVE; UNCLASSIFIED DRUG; ACRB PROTEIN, E COLI; ANTIINFECTIVE AGENT; MBX2319; MULTIDRUG RESISTANCE PROTEIN; PYRAN DERIVATIVE;

ANTIBACTERIAL ACTIVITY; ARTICLE; BACTERIAL STRAIN; BINDING AFFINITY; CARBOXY TERMINAL SEQUENCE; CONFORMATION; CONTROLLED STUDY; CRYSTAL STRUCTURE; DRUG BINDING; DRUG BINDING SITE; DRUG DESIGN; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG RELEASE; DRUG STABILITY; DRUG STRUCTURE; ENZYME INHIBITION; HYDROGEN BOND; HYDROPHOBICITY; MOLECULAR DYNAMICS; MOLECULAR INTERACTION; MOLECULAR STABILITY; NONHUMAN; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN STRUCTURE; ANTAGONISTS AND INHIBITORS; BINDING SITE; CHEMICAL PHENOMENA; CHEMISTRY; DRUG DEVELOPMENT; DRUG EFFECTS; ESCHERICHIA COLI; HUMAN; METABOLISM; MOLECULAR MODEL; MULTIDRUG RESISTANCE; PROTEIN TERTIARY STRUCTURE; X RAY CRYSTALLOGRAPHY;

ANTI-BACTERIAL AGENTS; BINDING SITES; CRYSTALLOGRAPHY, X-RAY; DRUG DISCOVERY; DRUG RESISTANCE, MULTIPLE, BACTERIAL; ESCHERICHIA COLI; ESCHERICHIA COLI PROTEINS; HUMANS; HYDROPHOBIC AND HYDROPHILIC INTERACTIONS; MODELS, MOLECULAR; MOLECULAR DYNAMICS SIMULATION; MULTIDRUG RESISTANCE-ASSOCIATED PROTEINS; PROTEIN STRUCTURE, TERTIARY; PYRANS; PYRIDINES;

EID: 84962163284     PISSN: 00278424     EISSN: 10916490     Source Type: Journal    
DOI: 10.1073/pnas.1602472113     Document Type: Article

References (31)

1. Li XZ, Plésiat P, Nikaido H (2015) The challenge of efflux-mediated antibiotic resistance in Gram-negative bacteria. Clin Microbiol Rev 28(2):337-418.
2. Ruggerone P, Murakami S, Pos K.M., Vargiu AV (2013) RND efflux pumps: Structural information translated into function and inhibition mechanisms. Curr Top Med Chem 13(24):3079-3100.
3. Du D, van Veen HW, Murakami S, Pos KM, Luisi BF (2015) Structure, mechanism and cooperation of bacterial multidrug transporters. Curr Opin Struct Biol 33:76-91.
4. Du D, et al. (2014) Structure of the AcrAB-TolC multidrug efflux pump. Nature 509 (7501):512-515.
5. Murakami S, Nakashima R, Yamashita E., Matsumoto T, Yamaguchi A (2006) Crystal structures of a multidrug transporter reveal a functionally rotating mechanism. Nature 443 (7108):173-179.
6. Seeger MA, et al. (2006) Structural asymmetry of AcrB trimer suggests a peristaltic pump mechanism. Science 313 (5791):1295-1298.
7. Sennhauser G, Amstutz P, Briand C., Storchenegger O, Grütter MG (2007) Drug export pathway of multidrug exporter AcrB revealed by DARPin inhibitors. PLoS Biol 5(1):e7.
8. Seeger MA, et al. (2008) Engineered disulfide bonds support the functional rotation mechanism of multidrug efflux pump Acr B. Nat Struct Mol Biol 15(2):199-205.
9. Nakashima R, Sakurai K, Yamasaki S., Nishino K, Yamaguchi A (2011) Structures of the multidrug exporter AcrB reveal a proximal multisite drug-binding pocket. Nature 480 (7378):565-569.
10. Eicher T, et al. (2014) Coupling of remote alternating-access transport mechanisms for protons and substrates in the multidrug efflux pump Acr B. eLife 3:1-26.
11. Pos KM (2009) Drug transport mechanism of the AcrB efflux pump. Biochim Biophys Acta 1794(5):782-793.
12. Su C-C, et al. (2006) Conformation of the AcrB multidrug efflux pump in mutants of the putative proton relay pathway. J Bacteriol 188(20):7290-7296.
13. Dreier J, Ruggerone P (2015) Interaction of antibacterial compounds with RND efflux pumps in Pseudomonas aeruginosa. Front Microbiol 6:660.
14. Opperman TJ, Nguyen ST (2015) Recent advances toward a molecular mechanism of efflux pump inhibition. Front Microbiol 6:421.
15. Lomovskaya O, et al. (2001) Identification and characterization of inhibitors of multidrug resistance efflux pumps in Pseudomonas aeruginosa: Novel agents for combination therapy. Antimicrob Agents Chemother 45(1):105-116.
16. Lomovskaya O, Bostian KA (2006) Practical applications and feasibility of efflux pump inhibitors in the clinic-a vision for applied use. Biochem Pharmacol 71(7):910-918.
17. Bohnert JA, Kern WV (2005) Selected arylpiperazines are capable of reversing multidrug resistance in Escherichia coli overexpressing RND efflux pumps. Antimicrob Agents Chemother 49(2):849-852.
18. Yoshida K, et al. (2007) MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 7: Highly soluble and in vivo active quaternary ammonium analogue D13-9001, a potential preclinical candidate. Bioorg Med Chem 15(22):7087-7097.
19. Yamaguchi A, Nakashima R, Sakurai K (2015) Structural basis of RND-type multidrug exporters. Front Microbiol 6:327.
20. Nakashima R, et al. (2013) Structural basis for the inhibition of bacterial multidrug exporters. Nature 500 (7460):102-106.
21. Opperman TJ, et al. (2014) Characterization of a novel pyranopyridine inhibitor of the AcrAB efflux pump of Escherichia coli. Antimicrob Agents Chemother 58(2):722-733.
22. Nguyen ST, et al. (2015) Structure-activity relationships of a novel pyranopyridine series of Gram-negative bacterial efflux pump inhibitors. Bioorg Med Chem 23(9):2024-2034.
23. Eicher T, et al. (2012) Transport of drugs by the multidrug transporter AcrB involves an access and a deep binding pocket that are separated by a switch-loop. Proc Natl Acad Sci USA 109(15):5687-5692.
24. Murakami S, Nakashima R, Yamashita E., Yamaguchi A (2002) Crystal structure of bacterial multidrug efflux transporter Acr B. Nature 419 (6907):587-593.
25. Takatsuka Y, Chen C, Nikaido H (2010) Mechanism of recognition of compounds of diverse structures by the multidrug efflux pump AcrB of Escherichia coli. Proc Natl Acad Sci USA 107(15):6559-6565.
26. Vargiu AV, Nikaido H (2012) Multidrug binding properties of the AcrB efflux pump characterized by molecular dynamics simulations. Proc Natl Acad Sci USA 109(50):20637-20642.
27. Vargiu AV, Ruggerone P, Opperman T.J., Nguyen ST, Nikaido H (2014) Molecular mechanism of MBX2319 inhibition of Escherichia coli AcrB multidrug efflux pump and comparison with other inhibitors. Antimicrob Agents Chemother 58(10):6224-6234.
28. Vargiu AV, et al. (2011) Effect of the F610A mutation on substrate extrusion in the AcrB transporter: Explanation and rationale by molecular dynamics simulations. J Am Chem Soc 133(28):10704-10707.
29. Grey JL, Thompson DH (2010) Challenges and opportunities for new protein crystallization strategies in structure-based drug design. Expert Opin Drug Discov 5(11):1039-1045.
30. Geertsma ER, Dutzler R (2011) A versatile and efficient high-throughput cloning tool for structural biology. Biochemistry 50(15):3272-3278.
31. Nagano K, Nikaido H (2009) Kinetic behavior of the major multidrug efflux pump AcrB of Escherichia coli. Proc Natl Acad Sci USA 106(14):5854-5858.