A Comparative Computational Analysis Approach to Predict Significant
Protein-Protein Interactions of Human and Vancomycin Resistant Enterococcus
faecalis (VRE) to Prioritize Potential Drug Targets

Reaz      Uddin; Kanwal      Khan

doi:10.2174/1570180818666211006125332

Abstract

Background: Various challenges exist in the treatment of infectious diseases due to the significant rise in drug resistance, resulting in the failure of antibiotic treatment. As a consequence, a dire need has arisen for the rethinking of the drug discovery cycle because of the challenge of drug resistance. The underlying cause of the infectious diseases depends upon associations within the Host-pathogen Protein- Protein Interactions (HP-PPIs) network, which represents a key to unlock new pathogenesis mechanisms. Hence, the elucidation of significant PPIs is a promising approach for the identification of potential drug targets.

Objective: Identification of the most significant HP-PPIs and their partners, and targeting them to prioritize potential new drug targets against Vancomycin-resistant Enterococcus faecalis (VRE).

Methods: We applied a computational approach based on one of the emerging techniques i.e. Interolog methodology to predict the significant Host-Pathogen PPIs. Structure-Based Studies were applied to model shortlisted protein structures and validate them through PSIPRED, PROCHECK, VERIFY3D, and ERRAT tools. Furthermore, 18,000 drug-like compounds from the ZINC library were docked against these proteins to study protein-chemical interactions using the AutoDock based molecular docking method.

Results: The study resulted in the identification of 118 PPIs for Enterococcus faecalis, and prioritized two novel drug targets i.e. Exodeoxyribonuclease (ExoA) and ATP-dependent Clp protease proteolytic subunit (ClpP). Consequently, the docking program ranked 2,670 and 3,154 compounds as potential binders against Exodeoxyribonuclease and ATP-dependent Clp protease proteolytic subunit, respectively.

Conclusion: Thereby, the current study enabled us to identify and prioritize potential PPIs in VRE and their interacting proteins in human hosts along with the pool of novel drug candidates.

Keywords: Vancomycin-resistant enterococci (VRE), Enterococcus faecalis, protein-protein interactions, interolog methodology, exodeoxyribonuclease, ATP-dependent Clp protease proteolytic subunit.

« Previous Next »

Graphical Abstract

[1] 
Murray, B.E. The life and times of the Enterococcus. Clin. Microbiol. Rev.,  1990, 3(1), 46-65.
[http://dx.doi.org/10.1128/CMR.3.1.46] [PMID:  2404568] 
[2] 
Hollenbeck, B.L.; Rice, L.B. Intrinsic and acquired resistance mechanisms in enterococcus. Virulence,  2012, 3(5), 421-433.
[http://dx.doi.org/10.4161/viru.21282] [PMID:  23076243] 
[3] 
Farrow, J.A.; Collins, M.D. DNA base composition, DNA-DNA homology and long-chain fatty acid studies on Streptococcus thermophilus and Streptococcus salivarius. J. Gen. Microbiol.,  1984, 130(2), 357-362.
[PMID:  6726177] 
[4] 
Global antimicrobial resistance surveillance system ( GLASS) report: Early implementation 2017-2018. World Health Organization, 2018.
[5] 
Nicod, C.; Banaei-Esfahani, A.; Collins, B.C. Elucidation of host-pathogen protein-protein interactions to uncover mechanisms of host cell rewiring. Curr. Opin. Microbiol.,  2017, 39, 7-15.
[http://dx.doi.org/10.1016/j.mib.2017.07.005] [PMID:  28806587] 
[6] 
Uddin, R.; Jamil, F. Prioritization of potential drug targets against P. aeruginosa by core proteomic analysis using computational subtractive genomics and Protein-Protein interaction network. Comput. Biol. Chem.,  2018, 74, 115-122.
[http://dx.doi.org/10.1016/j.compbiolchem.2018.02.017] [PMID:  29587180] 
[7] 
Pieters, J.; Gatfield, J. Hijacking the host: survival of pathogenic mycobacteria inside macrophages. Trends Microbiol.,  2002, 10(3), 142-146.
[http://dx.doi.org/10.1016/S0966-842X(02)02305-3] [PMID:  11864824] 
[8] 
Dye, M.D.; Neff, C.; Dufford, M.; Rivera, C.G.; Shattuck, D.; Bassaganya-Riera, J. The human-bacterial pathogen protein interaction networks of Bacillus anthracis, Francisella tularensis, and Yersinia pesti. PLoS One,  2010, 5(8), e120899.
[9] 
Wu, X.; Zhu, L.; Guo, J.; Zhang, D-Y.; Lin, K. Prediction of yeast protein-protein interaction network: insights from the Gene Ontology and annotations. Nucleic Acids Res.,  2006, 34(7), 2137-2150.
[http://dx.doi.org/10.1093/nar/gkl219] [PMID:  16641319] 
[10] 
Matthews, L.R.; Vaglio, P.; Reboul, J.; Ge, H.; Davis, B.P.; Garrels, J.; Vincent, S.; Vidal, M. Identification of potential interaction networks using sequence-based searches for conserved protein-protein interactions or “interologs”. Genome Res.,  2001, 11(12), 2120-2126.
[http://dx.doi.org/10.1101/gr.205301] [PMID:  11731503] 
[11] 
Ng, S-K.; Zhang, Z.; Tan, S-H. Integrative approach for computationally inferring protein domain interactions. Bioinformatics,  2003, 19(8), 923-929.
[http://dx.doi.org/10.1093/bioinformatics/btg118] [PMID:  12761053] 
[12] 
Flores-Mireles, A.L.; Pinkner, J.S.; Caparon, M.G.; Hultgren, S.J. EbpA vaccine antibodies block binding of Enterococcus faecalis to fibrinogen to prevent catheter-associated bladder infection in mice. Sci. Transl. Med.,  2014, 6(254), 254ra127.
[http://dx.doi.org/10.1126/scitranslmed.3009384] 
[13] 
Nielsen, H.V.; Guiton, P.S.; Kline, K.A.; Port, G.C.; Pinkner, J.S.; Neiers, F.; Normark, S.; Henriques-Normark, B.; Caparon, M.G.; Hultgren, S.J. The metal ion-dependent adhesion site motif of the Enterococcus faecalis EbpA pilin mediates pilus function in catheter-associated urinary tract infection. MBio,  2012, 3(4), e00177-e12.
[http://dx.doi.org/10.1128/mBio.00177-12] [PMID:  22829678] 
[14] 
Liu, Z-P.; Chen, L. Proteome-wide prediction of protein-protein interactions from high-throughput data. Protein Cell,  2012, 3(7), 508-520.
[http://dx.doi.org/10.1007/s13238-012-2945-1] [PMID:  22729399] 
[15] 
Casadevall, A.; Pirofski, L.A. Host-pathogen interactions: redefining the basic concepts of virulence and pathogenicity. Infect. Immun.,  1999, 67(8), 3703-3713.
[http://dx.doi.org/10.1128/IAI.67.8.3703-3713.1999] [PMID:  10417127] 
[16] 
Shoemaker, B.A.; Panchenko, A.R. Deciphering protein-protein interactions. Part II. Computational methods to predict protein and domain interaction partners. PLOS Comput. Biol.,  2007, 3(4), e43.
[http://dx.doi.org/10.1371/journal.pcbi.0030043] [PMID:  17465672] 
[17] 
Krishnadev, O.; Srinivasan, N. Prediction of protein-protein interactions between human host and a pathogen and its application to three pathogenic bacteria. Int. J. Biol. Macromol.,  2011, 48(4), 613-619.
[http://dx.doi.org/10.1016/j.ijbiomac.2011.01.030] [PMID:  21310175] 
[18] 
Arnold, R.; Boonen, K.; Sun, M.G.; Kim, P.M. Computational analysis of interactomes: current and future perspectives for bioinformatics approaches to model the host-pathogen interaction space. Methods,  2012, 57(4), 508-518.
[http://dx.doi.org/10.1016/j.ymeth.2012.06.011] [PMID:  22750305] 
[19] 
Uddin, R.; Zahra, N.U.; Azam, S.S. Identification of glucosyl-3-phosphoglycerate phosphatase as a novel drug target against resistant strain of Mycobacterium tuberculosis (XDR1219) by using comparative metabolic pathway approach. Comput. Biol. Chem.,  2019, 79, 91-102.
[http://dx.doi.org/10.1016/j.compbiolchem.2019.01.011] [PMID:  30743161] 
[20] 
Uddin, R.; Tariq, S.S.; Azam, S.S.; Wadood, A.; Moin, S.T. Identification of Histone Deacetylase (HDAC) as a drug target against MRSA via interolog method of protein-protein interaction prediction. Eur. J. Pharm. Sci.,  2017, 106, 198-211.
[http://dx.doi.org/10.1016/j.ejps.2017.06.003] [PMID:  28591562] 
[21] 
Tyagi, N.; Krishnadev, O.; Srinivasan, N. Prediction of protein-protein interactions between Helicobacter pylori and a human host. Mol. Biosyst.,  2009, 5(12), 1630-1635.
[http://dx.doi.org/10.1039/b906543c] [PMID:  20023722] 
[22] 
Krishnadev, O A data integration approach to predict host-pathogen protein-protein interactions: application to recognize protein interactions between human and a malarial parasite. Int J Biol Macromol,  2008, 8(3,4), 235-250.
[23] 
Rain, J-C.; Selig, L.; De Reuse, H.; Battaglia, V.; Reverdy, C.; Simon, S.; Lenzen, G.; Petel, F.; Wojcik, J. Sch‰chter, V.; Chemama, Y.; Labigne, A.; Legrain, P. The protein-protein interaction map of Helicobacter pylori. Nature,  2001, 409(6817), 211-215.
[http://dx.doi.org/10.1038/35051615] [PMID:  11196647] 
[24] 
Davis, F.P.; Barkan, D.T.; Eswar, N.; McKerrow, J.H.; Sali, A. Host pathogen protein interactions predicted by comparative modeling. Protein Sci.,  2007, 16(12), 2585-2596.
[http://dx.doi.org/10.1110/ps.073228407] [PMID:  17965183] 
[25] 
Mondal, S.I.; Ferdous, S.; Jewel, N.A.; Akter, A.; Mahmud, Z.; Islam, M.M.; Afrin, T.; Karim, N. Identification of potential drug targets by subtractive genome analysis of Escherichia coli O157:H7: an in silico approach. Adv. Appl. Bioinform. Chem.,  2015, 8, 49-63.
[http://dx.doi.org/10.2147/AABC.S88522] [PMID:  26677339] 
[26] 
Moreno-Cinos, C.; Goossens, K.; Salado, I.G.; Van Der Veken, P.; De Winter, H.; Augustyns, K. ClpP protease, a promising antimicrobial target. Int. J. Mol. Sci.,  2019, 20(9), 2232.
[http://dx.doi.org/10.3390/ijms20092232] [PMID:  31067645] 
[27] 
Hawser, S.; Lociuro, S.; Islam, K. Dihydrofolate reductase inhibitors as antibacterial agents. Biochem. Pharmacol.,  2006, 71(7), 941-948.
[http://dx.doi.org/10.1016/j.bcp.2005.10.052] [PMID: 16359642] 

Rights & Permissions Print Cite

Article Metrics

14

1

Explore Articles

Open Access

Open Access Articles

DOI https://dx.doi.org/10.2174/1570180818666211006125332	Print ISSN 1570-1808
Publisher Name Bentham Science Publisher	Online ISSN 1875-628X

Letters in Drug Design & Discovery

A Comparative Computational Analysis Approach to Predict Significant Protein-Protein Interactions of Human and Vancomycin Resistant Enterococcus faecalis (VRE) to Prioritize Potential Drug Targets

Abstract Play Pause

Graphical Abstract

Abstract