Exploring the significance of diaminopimelate epimerase as a drug target in multidrug resistant Enterococcus faecalis

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Review Articles | Published:

Print ISSN : 0970-4078.
Online ISSN : 2229-4473.
Website:www.vegetosindia.org
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Doi: 10.1007/s42535-022-00485-1
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Keywords: Enterococcus faecalis , MDR bacteria, Diaminopimelate epimerase, Drug design


Abstract


Enterococcus faecalis (E. faecalis) is a Gram-positive multidrug-resistant bacterium that is involved in almost 75% of all nosocomial infections. Most E. faecalis infections occur as a result of the use of E. faecalis harboring intravascular devices. The most common infections caused by E. faecalis are urinary tract infections, surgical site infections, and endocarditis. E. faecalis has a tendency to make biofilms on medical devices which makes it even more difficult to treat. Due to multidrug resistance nature of E. faecalis, it is now becoming essential to develop new compounds having antimicrobial activity. Therefore, it is necessary to target important proteins which are essential for the survival of E. faecalis and develop compounds that can bind and inhibit the activity of such proteins In E. faecalis, diaminopimelate epimerase (DapF) is an important enzyme involved in the metabolism of the amino acids lysine and mesoDap. Both of these metabolites are important as they have a significant role in several metabolic processes of bacteria such as peptidoglycan biosynthesis, synthesis of house-keeping proteins, and synthesis of other bacterial virulence factors. In a pathway involving the conversion of aspartate to lysine, DapF specifically catalyzes the isomerization of L, L- diaminopimelate to meso-DAP. This review provides a comprehensive overview of the structural and functional correlations of E. faecalis DapF. It provides a comparative structural analysis of DapF from E. faecalis and other pathogenic bacterial species. We have also emphasized on the existing approaches, paradoxes, and the prospects for the identification of potential inhibitors of E. faecalis DapF for treatment of E. faecalis infections.

Graphical abstract



              Enterococcus faecalis
            , MDR bacteria, Diaminopimelate epimerase, Drug design


References


Alam P, Chaturvedi SK, Anwar T et al (2015) Biophysical and molecular docking insight into the interaction of cytosine β-D arabinofuranoside with human serum albumin. J Lumin 164:123–130. https://doi.org/10.1016/J.JLUMIN.2015.03.011.28


Beganovic M, Luther MK, Rice LB, Arias CA, Rybak MJ, LaPlante KL (2018) A review of combination antimicrobial therapy for Enterococcus faecalis bloodstream infections and infective endocarditis. Clin Infect Dis 67(2):303–309


Blankenfeldt W, Kuzin AP, Skarina T, Korniyenko Y, Tong L, Bayer P, Janning P, Thomashow LS, Mavrodi DV (2004) Structure and function of the phenazine biosynthetic protein PhzF from Pseudomonas fluorescens. Proc Natl Acad Sci USA 101:16431–16436


Born TL, Blanchard JS (1999) Structure/function studies on enzymes in the diaminopimelate pathway of bacterial cell wall biosynthesis. Curr Opin Chem Biol 3:607–613


Buschiazzo A, Goytia M, Schaeffer F, Degrave W, Shepard W, Gregoire C et al (2006) Proc Natl Acad Sci USA 103:1705–1710


Caspi R, Altman T, Billington R, Dreher K, Foerster H, Fulcher CA, Holland TA, Keseler IM, Kothari A et al (2014) The MetaCyc database of metabolic pathways and enzymes and the BioCyc collection of pathway/genome databases. Nucleic Acids Res 44(D1):D471–D480


Choi CH (2005) ABC transporters as multidrug resistance mechanisms and the development of chemosensitizers for their reversal. Cancer Cell Int. https://doi.org/10.1186/1475-2867-5-30


Cirilli M, Zheng R, Scapin G, Blanchard JS (1998) Structural symmetry: the three-dimensional structure of Haemophilus influenzae diaminopimelate epimerase. Biochemistry-US 37:16452–16458. https://doi.org/10.2210/PDB1BWZ/PDB


Cirillo JD, Weisbrod TR, Banerjee A, Bloom BR, Jacobs WR Jr (1994) Genetic determination of the meso diaminopimelate biosynthetic pathway of mycobacteria. J Bacteriol 176:4424–4429


Cox RJ, Sutherland A, Vederas JC (2000) Bacterial diaminopimelate metabolism as a target for antibiotic design. Bioorg Med Chem 8(5):843871. https://doi.org/10.1016/S0968-0896(00)00044-4


Dantas G, Sommer MOA, Oluwasegun RD, Church GM (2008) Bacteria subsisting on antibiotics. Science 320(5872):100–103. https://doi.org/10.1126/science.1155157


D’Costa VM (2006) Sampling the antibiotic resistome. Science 311(5759):374–377. https://doi.org/10.1126/science.1120800


Diaper CM, Sutherland A, Pillai B, James MNG, Semchuk P, Blanchard JS, Vederas JC (2005) The stereoselective synthesis of aziridine analogues of diaminopimelic acid (DAP) and their interaction with dap epimerase. Org Biomol Chem 3:4402


Fernández- Hidalgo N, Almirante B, Gavaldà J, Gurgui M, Peña C, de Alarcón A, Pahissa A (2013) Ampicillin plus ceftriaxone is as effective as ampicillin plus gentamicin for treating Enterococcus faecalis infective endocarditis. Clin Infect Dis 56(9):1261–1268. https://doi.org/10.1093/cid/cit052


Fisher K, Carol P (2009) The ecology, epidemiology and virulence of enterococcus. Microbiology 155:1749–1757. https://doi.org/10.1099/mic.0.026385-0.2


Franklin TJ, Snow GA (2005) Biochemistry and molecular biology of antimicrobial drug action. Springer Science & Business Media


Garvey GS, Rocco CJ, Escalante-Semerena JC, Rayment I (2007) The three-dimensional crystal structure of the PrpF protein of Shewanella oneidensis complexed with trans-aconitate: insights into its biological function. Protein Sci 16:1274–1284


Gerhart F, Higgins W, Tardif C, Ducep JBJ (1990) Construction of N- alkyl- and N- arylaziridines from unprotected amines via C−H oxidative amination strategy. Med Chem 33:2157


Hall RM, Stokes HW (1993) Integrons: Novel DNA elements which capture genes by site- specific recombination. Genetica 90(2–3):115–132. https://doi.org/10.1007/BF01435034


Higgins CF (2007) Multiple molecular mechanisms for multidrug resistance transporters. Nature 446(7137):749–757. https://doi.org/10.1038/nature05630


Hollenbeck BL, Rice LB (2012) Intrinsic and acquired resistance mechanisms in Enterococcus. Virulence 3(5):421–433. https://doi.org/10.4161/viru.21282


Hor L, Dobson RCJ, Downton MT, Wagner J, Hutton CA, Perugini MA (2013) Dimerization of bacterial diaminopimelate epimerase is essential for catalysis. J Biol Chem 288(13):9238–9248. https://doi.org/10.1074/jbc.M113.450148


Hudson AO, Bless C, Macedo P, Chatterjee SP, Singh BK, Gilvarg C, Leustek T (2005) Biosynthesis of lysine in plants: evidence for a variant of the known bacterial pathways. Biochim Biophys Acta 1721:27–36


Hutton CA, Perugini MA, Gerrard JA (2007) Inhibition of lysine biosynthesis: an evolving antibiotic strategy. Mol Biosyst 3(7):458–465. https://doi.org/10.1039/b705624a


Hutton C, Southwood T, Turner J (2003) Inhibitors of lysine biosynthesis as antibacterial agents. Mini-Rev Med Chem 3(2):115–127. https://doi.org/10.2174/1389557033405359


Kim SJ (2015) Chang J & Singh M (2015) Peptidoglycan architecture of Gram-positive bacteria by solid-state NMR. Biochem Biophys Acta 1848(1 Pt B):350–362


Kristich CJ, Rice LB, Arias CA (2014) Enterococcal infection—treatment and antibiotic resistance. Enterococci: from commensals to leading causes of drug resistant infection. Massachusetts Eye and Ear Infirmary, Boston, MA


Lam LKP, Arnold LD, Kalantar TH, Kelland JG, Lane-Bell PM, Palcic MM, Pickard MA, Vederas JCJ (1988) Biol Chem 1988(263):11814


Laskar K, Alam P, Khan R, Rauf A (2016) Synthesis, characterization and interaction studies of 1,3,4-oxadiazole derivatives of fatty acid with human serum albumin (HSA): a combined multi-spectroscopic and molecular docking study. Eur J Med Chem 122:72–78. https://doi.org/10.1016/J.EJMECH.2016.06.012


Lebreton F, Willems RJL, Gilmore MS (2014) Enterococcus diversity, origins in nature, and gut colonization. Massachusetts Eye and Ear Infirmary, Boston


Li XZ, Nikaido H (2009) Efflux- mediated drug resistance in bacteria: an update. Drugs 69(12):1555–1623. https://doi.org/10.2165/11317030-000000000-00000


Lloyd AJ, Huyton T, Turkenburg J, Roper DI (2004) Refinement of Haemophilus influenzae diaminopimelic acid epimerase (DapF) at 1.75 Å resolution suggests a mechanism for stereocontrol during catalysis. Acta Crystallogr Sect D Biol Crystallogr 60(2):397–400. https://doi.org/10.1107/S0907444903027999


Matsuhashi M (1994) Utilization of lipid-linked precursors and the formation of peptidoglycan in the process of cell growth and division: membrane enzymes involved in the final steps of peptidoglycan synthesis and the mechanism of their regulation. In: Ghuysen JM, Hakenbeck R (eds) Bacterial cell wall. Elsevier Science, Amsterdam, the Netherlands, pp 55–71


Miller WR, Munita JM, Arias CA (2014) Mechanisms of antibiotic resistance in enterococci. Expert Rev Anti Infect Ther 12(10):1221–1236. https://doi.org/10.1586/14787210.2014.956092


Neher A, Arnitz R, Gstöttner M, Schä D, Kröss E-M, Nagl M (2008) Antimicrobial activity of dexamethasone and its combination with N-chlorotaurine. Arch Otolaryngol Head Neck Surg 134:615–620


Nigo M, Munita JM, Arias CA, Murray BE (2014) What’s new in the treatment of enterococcal endocarditis? Curr Infect Dis Rep 16(10):431. https://doi.org/10.1007/s11908-014-0431-z


Olawale K, Fadiora S, Taiwo S (2011) Prevalence of hospital acquired enterococci infections in two primary-care hospitals in Osogbo, Southwestern Nigeria. Afr J Infect Dis 5(2):40–46. https://doi.org/10.4314/ajid.v5i2.66513


Palmer KL, Kos VN, Gilmore MS (2010) Horizontal gene transfer and the genomics of enterococcal antibiotic resistance. Curr Opin Microbiol 13(5):632–639. https://doi.org/10.1016/j.mib.2010.08.004


Parsons JF, Song F, Parsons L, Calabrese K, Eisenstein E, Ladner JE (2004) Structure and function of the phenazine biosynthesis protein PhzF from Pseudomonas fluorescens 2–79. Biochemistry-US 43(39):12427–12435. https://doi.org/10.1021/bi049059z


Paulsen IT, Brown MH, Skurray RA (1996) Proton- dependent multidrug efflux systems. Microbiol Mol Biol R 60(4):575–608


Pillai B, Cherney MM, Diaper CM et al (2006) Structural insights into stereochemical inversion by diaminopimelate epimerase: an antibacterial drug target. Proc Natl Acad Sci U S A 103(23):8668–8673. https://doi.org/10.1073/pnas.0602537103


Pillai B, Moorthie VA, van Belkum MJ et al (2009) Crystal structure of Diaminopimelate Epimerase from Arabidopsis thaliana, an amino acid Racemase critical for l-lysine biosynthesis. J Mol Biol 385(2):580594. https://doi.org/10.1016/J.JMB.2008.10.072


Rajagopal M, Walker S (2017) Envelope structures of gram-positive bacteria. Microbiol Immunol 404:1–44. https://doi.org/10.1007/82_2015_5021


Rice LB (1998) Tn916 family conjugative transposons and dissemination of antimicrobial resistance determinants. Antimicrob Agents Ch 42(8):1871–1877. https://doi.org/10.1128/AAC.42.8.1871


Rowe- Magnus DA, Mazel D (2002) The role of integrons in antibiotic resistance gene capture. Int J Med Microbiol 292(2):115–125. https://doi.org/10.1078/1438-4221-00197


Sagong HY, Kim KJ (2017) Structural basis for redox sensitivity in Corynebacterium glutamicum diaminopimelate epimerase: an enzyme involved in llysine biosynthesis. Sci Rep. https://doi.org/10.1038/srep42318


Singh H, Das S, Yadav J, Srivastava VK, Jyoti A, Kaushik S (2019) In search of novel protein drug targets for treatment of Enterococcus faecalis infections. Chem Biol Drug Des 94(4):1721–1739


Singh H, Das S, Yadav J, Srivastava VK, Jyoti A, Kaushik S (2021) In silico prediction, molecular docking and binding studies of acetaminophen and dexamethasone to Enterococcus faecalis diaminopimelate epimerase. J Mol Recognit. https://doi.org/10.1002/jmr.2894


Skariyachan S, Manjunath M, Bachappanavar N (2019) Screening of potential lead molecules against prioritized targets of multi-drug-resistant-Acinetobacter baumannii - insights from molecular docking, molecular dynamic simulations and in vitro assays. J Biomol Struct Dyn 37(5):1146–1169


Toleman MA, Bennett PM, Walsh TR (2006) ISCR elements: Novel gene- capturing systems of the 21st century? Microbiol Mol Biol Rev 70(2):296–316. https://doi.org/10.1128/MMBR.00048-05


Tseng TT, Gratwick KS, Kollman J, Park D, Nies DH, Goffeau A, Saier MH (1999) The RND permease superfamily: an ancient, ubiquitous and diverse family that includes human disease and development proteins. J Mol Microbiol Biotechnol 1:107–125


Usha V, Dover LG, Roper DI, Fütterer K, Besra G (2009) Structure of the diaminopimelate epimerase DapF from Mycobacterium tuberculosis. Acta Crystallogr Sect D Biol Crystallogr 65(4):383–387. https://doi.org/10.1107/S0907444909002522


Van Harten RM, Willems RJL, Martin NI, Hendrickx APA (2017) Multidrug- resistant enterococcal infections: new compounds, novel antimicrobial therapies? Trends Microbiol 25(6):467–479. https://doi.org/10.1016/j.tim.2017.01.004


Vijayashree PJ (2019) In silico validation of the non-antibiotic drugs acetaminophen and ibuprofen as antibacterial agents against red complex pathogens. J Periodontol 90(12):1441–1448. https://doi.org/10.1002/JPER.18-0673


Zimmermann P, Curtis N (2017) Antimicrobial effects of antipyretics. Antimicrob Agents Chemother J Bacteriol 61(4):e02268-e2316. https://doi.org/10.1128/AAC.02268-16







 


Acknowledgements



Author Information


Chaudhary Jyoti
Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur, India

Singh Nagendra
School of Biotechnology, Gautam Buddha University, Greater Noida, India


Srivastava Vijay Kumar
Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur, India


Jyoti Anupam
Department of Biotechnology, UniversityInstituteofBiotechnology, Chandigarh University, Chandigarh, India


Kaushik Sanket
Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur, India
sanketkaushik@gmail.com