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3 Biotech

, 9:40 | Cite as

Designing quorum sensing inhibitors of Pseudomonas aeruginosa utilizing FabI: an enzymic drug target from fatty acid synthesis pathway

  • Manmohit Kalia
  • Vivek Kumar Yadav
  • Pradeep Kumar Singh
  • Suhaga Dohare
  • Deepmala Sharma
  • Shahid Suhail Narvi
  • Vishnu AgarwalEmail author
Original Article
  • 55 Downloads

Abstract

Pseudomonas aeruginosa infections are a leading cause of death in patients suffering from respiratory diseases. The multidrug-resistant nature of Pseudomonas is potentiated by a process known as quorum sensing. The aim of this study was to reveal new inhibitors of a well-validated but quite unexplored target, enoyl-ACP reductase, which contributes acyl chain lengths of N-acyl homoserine lactones that are major signaling molecules in gram-negative bacteria. In the present study, the crystal structure of FabI (PDB, ID 4NR0) was used for the structure-based identification of quorum sensing inhibitors of Pseudomonas aeruginosa. Active site residues of FabI were identified from the complex of FabI with triclosan and these active site residues were further used to screen for potential inhibitors from natural database. Three-dimensional structures of the 75 natural compounds were retrieved from the ZINC database and screened using PyRX software against FabI. Thirty-eight molecules from the initial screening were sorted on the basis of binding energy, using the known inhibitor triclosan as a standard. These molecules were subjected to various secondary filters, such as Lipinski’s Rule of Five, ADME, and toxicity. Finally, eight lead-like molecules were obtained after their evaluation for drug-like characteristics. The present study will open a new window for designing QS inhibitors against P. aeruginosa.

Keywords

Microbial drug resistance Quorum sensing Enoyl-ACP reductase Pseudomonas aeruginosa 

Notes

Acknowledgements

Authors are thankful to the Department of Science and Technology (DST), Department of Biotechnology, Government of India for facilitation and support.

Compliance with ethical standards

Conflict of interest

The authors have no conflicts of interest.

References

  1. Chirala SS, Huang WY, Jayakumar A et al (1997) Animal fatty acid synthase: functional mapping and cloning and expression of the domain I constituent activities. Proc Natl Acad Sci USA 94:5588–5593.  https://doi.org/10.1073/pnas.94.11.5588 CrossRefPubMedGoogle Scholar
  2. Costerton JW, Stewart SPGEP (1999) Bacterial biofilms: a common cause of persistent infections. Science 284:1318–1322.  https://doi.org/10.1126/science.284.5418.1318 CrossRefPubMedGoogle Scholar
  3. Daina A, Zoete V (2016) A BOILED-egg to predict gastrointestinal absorption and brain penetration of small molecules. Chem Med Chem 11:1117–1121.  https://doi.org/10.1002/cmdc.201600182 CrossRefPubMedGoogle Scholar
  4. Daina A, Michielin O, Zoete V (2014) iLOGP: a simple, robust, and efficient description of n-octanol/water partition coefficient for drug design using the GB/SA approach. J Chem Inf Model.  https://doi.org/10.1021/ci500467k CrossRefPubMedGoogle Scholar
  5. Dallakyan S, Olson AJ (2015) Small-molecule library screening by docking with PyRx. Mol Biol 1263:243–250.  https://doi.org/10.1007/978-1-4939-2269-7 CrossRefGoogle Scholar
  6. Fuente-nu D, Breidenstein EBM (2011) Pseudomonas aeruginosa: all roads lead to resistance. 19:419–426.  https://doi.org/10.1016/j.tim.2011.04.005
  7. Fuqua WC, Winans SC, Greenberg EP (1994) Quorum sensing in bacteria: the LuxR-LuxI family of cell density-responsive transcriptional regulators. J Bacteriol 176:269–275.  https://doi.org/10.1111/j.1462-5822.2006.00734.x CrossRefPubMedPubMedCentralGoogle Scholar
  8. Hoang TT, Schweizer HP (1999) Characterization of Pseudomonas aeruginosa enoyl-acyl carrier protein reductase (FabI): a target for the antimicrobial triclosan and its role in acylated homoserine lactone synthesis. J Bacteriol 181:5489–5497PubMedPubMedCentralGoogle Scholar
  9. Høiby N, Johansen HK, Moser C et al (2001) Pseudomonas aeruginosa and the in vitro and in vivo biofilm mode of growth. Microbes Infect 3:23–35CrossRefGoogle Scholar
  10. Irwin JJ, Shoichet BK (2005) ZINC-A free database of commercially available compounds for virtual screening. J Chem Inf Model 45:177–182CrossRefGoogle Scholar
  11. Koh CL1, Sam CK, Yin WF, Tan LY, Krishnan T, Chong YM, Chan KG (2013) Plant-derived natural products as sources of anti-quorum sensing compounds. Sensors 13:6217–6228.  https://doi.org/10.3390/s130506217 CrossRefPubMedGoogle Scholar
  12. LaSarre B, Federle MJ (2013) Exploiting quorum sensing to confuse bacterial pathogens. Microbiol Mol Biol Rev 77:73–111.  https://doi.org/10.1128/MMBR.00046-12 CrossRefPubMedPubMedCentralGoogle Scholar
  13. Lee J, Zhang L (2015) The hierarchy quorum sensing network in Pseudomonas aeruginosa. Protein Cell 6:26–41.  https://doi.org/10.1007/s13238-014-0100-x CrossRefPubMedGoogle Scholar
  14. Lee JH, Park AK, Chi YM, Jeong SW (2015) Crystal structures of Pseudomonas aeruginosa Enoyl-ACP reductase (FabI) in the presence and absence of NAD + and triclosan. Bull Korean Chem Soc 36:322–326.  https://doi.org/10.1002/bkcs.10084 CrossRefGoogle Scholar
  15. Lipinski CA (2004) Lead profiling lead- and drug-like compounds: the rule-of-five revolution. Drug Discov Today Technol 4:337–341.  https://doi.org/10.1016/j.ddtec.2004.11.007 CrossRefGoogle Scholar
  16. Lu H, Tonge PJ (2008) Inhibitors of Fabl, an enzyme drug target in the bacterial fatty acid biosynthesis pathway. Acc Chem Res 41:11–20.  https://doi.org/10.1021/ar700156e CrossRefPubMedGoogle Scholar
  17. Maunz A, Gütlein M, Rautenberg M et al (2013) lazar: a modular predictive toxicology framework. Front Pharmacol 4:1–10.  https://doi.org/10.3389/fphar.2013.00038 CrossRefGoogle Scholar
  18. Miller B (2001) Quorum sensing in bacteria. Annu Rev Microbiol 55:165–169CrossRefGoogle Scholar
  19. Moré MI, Finger LD, Stryker JL et al (1996) Enzymatic synthesis of a quorum-sensing autoinducer through use of defined substrates. Science 272:1655–1658.  https://doi.org/10.1126/science.272.5268.1655 CrossRefPubMedGoogle Scholar
  20. Morris GM, Huey R, Olson AJ (2008) Using AutoDock for ligand-receptor docking. Curr Protoc Bioinform 24:8–14Google Scholar
  21. Parikh S, Moynihan DP, Xiao G, Tonge PJ (1999) Roles of Tyrosine 158 and Lysine 165 in the catalytic mechanism of InhA, the enoyl-acp reductase from Mycobacterium tuberculosis. Biochemistry 38:13623–13634CrossRefGoogle Scholar
  22. Rozwarski DA, Vilchèze C, Sugantino M et al (1999) Crystal structure of the mycobacterium in complex with NAD + and a C16 fatty acyl substrate crystal structure of the mycobacterium tuberculosis enoyl-acp reductase, InhA, in complex with NAD+ and a C16 fatty acyl substrate. J Biol Chem 274:15582–15589.  https://doi.org/10.1074/jbc.274.22.15582 CrossRefPubMedGoogle Scholar
  23. Schweizer HP (2003) Efflux as a mechanism of resistance to antimicrobials in Pseudomonas aeruginosa and related bacteria: unanswered questions. Genet Mol Res 2:48–62PubMedGoogle Scholar
  24. Smith RS, Iglewski BH (2003) Pseudomonas aeruginosa quorum sensing as a potential antimicrobial target. J Clin Investig 112:1460–1465CrossRefGoogle Scholar
  25. Stewart MJ, Parikh S, Xiao G et al (1999) Structural basis and mechanism of enoyl reductase inhibition by triclosan. J Mol Biol 290:859–865.  https://doi.org/10.1006/jmbi.1999.2907 CrossRefPubMedGoogle Scholar
  26. Taylor PK, Yeung ATY, Hancock REW (2014) Antibiotic resistance in Pseudomonas aeruginosa biofilms: towards the development of novel anti-biofilm therapies. J Biotechnol 191:121–130CrossRefGoogle Scholar
  27. Trott O, Olson AJ (2009) Software news and update AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31:455–461.  https://doi.org/10.1002/jcc CrossRefGoogle Scholar
  28. White SW, Zheng J, Zhang Y, Rock CO (2005) Fatty acid biosynthesis. Rev Lit Arts Am 1:791–831.  https://doi.org/10.1146/annurev.biochem.74.082803.133524 CrossRefGoogle Scholar
  29. Yang L, Liu Y, Sternberg C, Molin S (2010) Evaluation of enoyl-acyl carrier protein reductase inhibitors as Pseudomonas aeruginosa quorum-quenching reagents. Molecules 15:780–792.  https://doi.org/10.3390/molecules15020780 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© King Abdulaziz City for Science and Technology 2019

Authors and Affiliations

  • Manmohit Kalia
    • 1
  • Vivek Kumar Yadav
    • 1
  • Pradeep Kumar Singh
    • 1
  • Suhaga Dohare
    • 1
  • Deepmala Sharma
    • 2
  • Shahid Suhail Narvi
    • 3
  • Vishnu Agarwal
    • 1
    Email author
  1. 1.Department of BiotechnologyMotilal Nehru National Institute of Technology AllahabadAllahabadIndia
  2. 2.Department of MathematicsNational Institute of Technology RaipurRaipurIndia
  3. 3.Department of ChemistryMotilal Nehru National Institute of Technology AllahabadAllahabadIndia

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