An Insight into Molecular Drug Targets of Helicobacter Pylori and Potential Therapies
Authors
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Department of Biotechnology, M S Ramaiah Institute of Technology, Bengaluru 560054, Karnataka ,IN
Shishira S Nair -
Department of Biotechnology, M S Ramaiah Institute of Technology, Bengaluru 560054, Karnataka ,INTP Krishna Murthy
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Department of Biotechnology, M S Ramaiah Institute of Technology, Bengaluru 560054, Karnataka ,ING Divyashri
DOI:
https://doi.org/10.18311/jmmf/2023/34736Keywords:
Helicobacter pylori, antibiotic resistance, drug targets, phytochemicalsAbstract
Helicobacter pylori are a gram-negative spiral-shaped bacterium, belonging to the class Epsilonproteobacteria that colonizes the gastric epithelium of humans leading to a common infection that affects nearly 50% of the total population across the globe. They are the common bacteria that evade the gastric tract of humans causing numerous pathologies such as chronic gastritis, peptic ulcers, gastric mucosa-associated lymphoid tissue (MALT) lymphoma and gastric cancer. Usually, treatment of H. pylori is carried out using two or three antibiotics combined with a proton pump inhibitor. Recently, there is an increase in antibiotic resistance throughout the world and henceforth, there is an immediate need in identifying effective treatments. Identifying specific targets in H. pylori that are responsible for host-pathogen interactions, virulence factors etc., and developing specific drugs against them is one of the potential solutions. In doing so, it is important to understand in depth the structure and functions of the targets to develop drugs that are specific to them. This would lead to the effective eradication of the infection. In this review, we have identified 10 potential targets which are Urease, FlgE2, HtrA, Chorismate synthase, Peptide deformylase, VacA, Adhesin BabA, Csd4, Flavodoxins, â-Clamp bound to DNA Ligase peptide. In future, effective drugs can be developed against these targets. Also, insights about the phytochemicals that are effective against H. pylori are mentioned in this review. Potential drugs combined with these phytochemicals can effectively eradicate the infection.
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References
Albert, A., Martinez-Ripoll, M., Espinosa-Ruiz, A., Yenush, L., CulianezMacia, F. A. and Serrano, R.,(2000): The X-ray structure of the FMN-binding protein AtHal3 provides the structural basis for the activity of a regulatory subunit involved in signal transduction. Structure, 8, 961-969.
Alm R A., Ling LS, Moir DT., et al., (1999): Genomic sequence comparison of two unrelated isolates of the human gastric pathogen Helicobacter pylori. Nature 1999; 397:176-80
Amin M., Anwar F., Naz F., Mehmood T., Saari N., (2013): Anti-Helicobacter pylori and urease inhibition activities of some traditional medicinal plants. Molecules 2013, 18, 2135-2149
Anson C. K. Chan., Kris M. Blair., Yanjie Liu., EmilisaFrirdich., Erin C. Gaynor., Martin E. Tanner., Nina R. Salama., and Michael E. P. Murphy., (2014): Helical Shape of Helicobacter pylori requires an A typical Glutamine as a Zinc Ligand in the Carboxypeptidase Csd4. JBC Vol. 290, No. 6, pp. 3622-3638.
Awaad A.S., Al-Rifai, A.A., El-Meligy, R.M., Alafeefy, A.M., Zain, M.E., (2015): New Activities for Isolated Compounds from Convolvulus austro-aegyptiacus as Anti-ulcerogenic, Anti-Helicobacter pylori and Their Mimic Synthesis Using Bio-guided Fractionation.
Bahare Salehi., FarukhSharopov., Miquel Martorell., Jovana Rajkovic., Adedayo OluwaseunAdemiluyi., Mehdi Sharifi-Rad., Patrick ValereTsouhFokou., Natália Martins., Marcello Iriti., and Javad Sharifi-Rad., (2018): Phytochemicals in Helicobacter pylori Infections: What Are We Doing Now?
Bergonzelli G.E., Donnicola D., Porta N., Corthésy-Theulaz I.E., (2003): Essential Oils as Components of a Diet-Based Approach to Management of Helicobacter Infection. Antimicrob. Agents Chemother. 47, 3240–3246.
Bjorkman DJ., Steenblik M., Best Practice Recommendations for Diagnosis and Management of Helicobacter pylori synthesizing the Guidelines. Dec; 15(4):648-659.
Castillo-Juarez I., Gonzalez V., Jaime-Aguilar H., Martinez G., Linares E., Bye R., Romero I., (2009): Anti-Helicobacter pylori activity of plants used in Mexican traditional medicine for gastrointestinal disorders. J. Ethnopharmacol. 122, 402–405.
Censini, S. et al., (1996): Cag pathogenicity island of Helicobacter pylori, encodes type I-specific and diseaseassociated virulence factors. Proc. Natl Acad. Sci. USA 93, 14648–14653.
Chambers MG, et al., (2013): Structural analysis of the oligomeric states of Helicobacter pyloriVacA toxin. J Mol Biol 425:524–535.
Cheng-Yen Kao., BorShyangSheu., Jiunn Jong Wu., (2016): Helicobacter pylori infection: An overview of bacterial virulence factors and pathogenesis. Biomedical journal 39 (2016) 14-23.
Clausen T., Kaiser M., Huber R., and Ehrmann M., (2011): HTRA proteases: regulated proteolysis in protein quality control. Nat. Struct. Mol. Biol. 12, 152-162.
Cogo L.L., Monteiro C.L.B., Miguel M.D., Miguel O.G., Cunico M.M., Ribeiro M.L., de Camargo E.R., Kussen G.M.B., Nogueira K.d.S., Costa L.M.D., (2010): Anti- Helicobacter pylori activity of plant extracts traditionally used for the treatment of gastrointestinal disorders. Braz. J. Microbiol. 41, 304–309.
Danielli A and Scarlato V., (2010): Regulatory circuits in Helicobacter pylori: network motifs and regulators involved in metal-dependent responses. FEMS Microbiol Rev 34, 738–752.
Donald R. Ronning., Natalie M. Iacopelli., and Vidhi Mishra., (2010): Enzyme–Ligand interactions that drive active site rearrangements in the Helicobacter pylori 5’methylthioadenosine/S-adenosylhomocysteine nucleosidase.
Escobedo-Hinojosa W.I., Del Carpio J.D., Palacios- Espinosa J.F., Romero I., (2012): Contribution to the ethno pharmacological and anti-Helicobacter pylori knowledge of Cyrtocarpaprocera Kunth (Anacardiaceae). J. Ethnopharmacol. 143, 363–371.
Falush D., Kraft C., Taylor NS., et al. (2001): Recombination and mutation during long-term gastric colonization by Helicobacter pylori: estimates of clock rates, recombination size, and minimal age. Proc Natl Acad Sci U S A; 98:15056-61.
Fukai T., Marumo A., Kaitou K., Kanda T., Terada S., Nomura T., (2002): Anti-Helicobacter pylori flavonoids from licorice extract. Life Sci. 71, 1449–1463.
Heuermann D., and R. Haas., (1995); Genetic organization of small cryptic plasmid of Helicobacter pylori. Gene 165:17–24.
Hosseininejad Z., Moghadam S.D., Ebrahimi F., Abdollahi M., Zahedi M.J., Nazari M., Hayatbakhsh M., Adeli S., Sharififar F., (2011): In vitro screening of selected Iranian medicinal plants against Helicobacter pylori. Int. J. Green Pharm. 5, 282–285.
Hyung Jun Ahn., Hye Jin Yoon., Byung Il Lee and Se Won Suh., (2004): Crystal Structure of Chorismate Synthase: A Novel FMN-binding Protein Fold and Functional Insights. J. Mol. Biol. 336, 903–915.
Hyoun Sook Kim., Jieun Kim., Ha Na Im., Doo Ri An., Mijoon Lee., DusanHesek., Shahriar Mobashery., Jin Young Kim., Kun Cho., Hye Jin Yoon., Byung Woo Han., Byung Il Leef and Se Won Suhb., (2014): Structural basis for the recognition of muramyl tripeptide by Helicobacter pylori Csd4, a D, L-Carboxypeptidase controlling the helical cell shape. ActaCryst. D70, 2800–2812.
Jain P., Luo Z-Q., Blanke SR., (2011): Helicobacter pylori vacuolating cytotoxin A (VacA) engages the mitochondrial fission machinery to induce host cell death. Proc Natl AcadSci USA 108:16032–16037.
Johannes G. Kusters., Arnoud H. M. van Vliet., and Ernst J. Kuipers., (2006): Pathogenesis of Helicobacter pylori Infection. p. 449–490.
Kaiming Zhang., Huawei Zhang., Shanshan Li., Grigore D. Pintilie., Tung-Chung Mou., Yuanzhu Gao., Qinfen Zhang., Henry van den Bedem., Michael F. Schmid., Shannon Wing Ngor Au., and Wah Chiu., (2019): Cryo- EM structures of Helicobacter pylori vacuolating cytotoxin A oligomeric assemblies at near-atomic resolution. PNAS 116 (14) 6800-6805.
Kansau I., J. Raymond., E. Bingen., P. Courcoux., N. Kalach., M. Bergeret., N. Briami., C. Dupont., and A. Labigne., (1996): Genotyping of Helicobacter pylori isolates by sequencing of PCR products and comparison with the RAPD technique. Res. Microbiol. 147:661–669.
Kris M. Blair., Kevin S. Mears., Jennifer A. Taylor., Jutta Fero., Lisa A. Jones., Philip R. Gafken., John C. Whitney., Nina R. Salama., (2021): The Helicobacter pylori cell shape promoting protein Csd5 interacts with the cell wall, MurF, and the bacterial cytoskeleton.
Kusters J. G., M. M. Gerrits., J. A. Van Strijp., and C. M. Vandenbroucke Grauls., (1997): Coccoid forms of Helicobacter pylori are the morphologic manifestation of cell death. Infect.Immun. 65:3672–3679.
Lertsethtakarn P., Ottemann KM and Hendrixson DR., (2011): Motility and chemotaxis in Campylobacter and Helicobacter. Annu Rev Microbiol 65, 389–410.
Li Y., Xu C., Zhang Q., Liu J.Y., Tan R.X., (2005): In vitro anti-Helicobacter pylori action of 30 Chinese herbal medicines used to treat ulcer diseases. J. Ethnopharmacol. 98, 329–333.
Liechti G., Goldberg JB., (2012): Helicobacter pylori rely primarily on the purine salvage pathway for purine nucleotide biosynthesis. J Bacteriol 194:839–854.
Mahady G.B., Pendland S.L., Stoia A., Chadwick L.R., (2003): In vitro susceptibility of Helicobacter pylori to isoquinoline alkaloids from Sanguinaria canadensis and Hydrastis canadensis. Phytother. Res. 17, 217–221.
Malaty HM., Graham DY., (1994): Importance of childhood socioeconomic status on the current prevalence of Helicobacter pylori infection. 35:742-5.
Malfertheiner P., Megraud F., O’Morain CA., et al., (2017): Management of Helicobacter pylori infection the Maastricht V/Florence Consensus Report. Jan; 66(1):6- 30.
Muhammad Dawood., Nighat Fatima., Amara Mumtaz., Sidra Rehman., IrumShazadi., Qaisar Mahmood and Syed Aun Muhammad., (2016): Molecular Docking Studies of Sesquiterpenoids against Helicobacter pylori Peptide Deformylase. BJPR. 10(3): 1-7.
N. Hage., J. G. Renshaw., G. S. Winkler., P. Gellert., S. Stolnik., F. H. Falcone., (2015): Improved expression and purification of the Helicobacter pylori adhesin BabA through the incorporation of a hexa lysine tag. Protein Expr. Purif. 106, 25–30.
NaimHage., Tina Howard., Chris Phillips., Claire Brassington., Ross Overman., JuditDebreczeni., Paul Gellert., Snow Stolnik., G. Sebastiaan Winkler., Franco H. Falcone., (2015): Structural basis of Lewisbantigen binding by the Helicobacter pylori adhesin BabA. Sci. Adv. 1:e1500315.
Nam Chul Ha., Sang Taek Oh., Jae Young Sung., Kyeung Ah Cha., (2001): Mann Hyung Lee and Byung Ha Oh., Supramolecular assembly and acid resistance of Helicobacter pylori urease.
Nariman F., Eftekhar F., Habibi Z., Falsafi T., (2004): Anti- Helicobacter pylori activities of six Iranian plants. 9, 146– 151.
Nariman F., Eftekhar F., Habibi Z., Massarrat S., Malekzadeh R., (2009): Antibacterial activity of twenty Iranian plant extracts against clinical isolates of Helicobacter pylori. Iran. J. Basic Med. Sci. 12, 105–111.
Nostro A., Cellini L., Bartolomeo S.D., Campli E.D., Grande R., Cannatelli M., Marzio L., Alonzo V., (2005): Antibacterial effect of plant extracts against Helicobacter pylori. Phytother. Res. 19, 198–202.
O’Morain NR., Dore MP., O’Connor AJP., Gisbert JP., O’Morain CA., (2018): Treatment of Helicobacter pylori infection. 23:1–9.
Parkhill J., Wren B., Mungall K., Ketley JM., Churcher C., Basham D., Chilling worth T., Davies RM., Feltwell T., Holroyd S et al., (2000): The genome sequence of the food borne pathogen Campylobacter jejuni reveals hypervariable sequences. Nature 403, 655–668.
Paul K., Gonzalez-Bonet G., Bilwes AM., Crane BR and Blair D., (2011): Architecture of the flagellar rotor. EMBO J 30, 2962–2971.
Paula RoszczenkoJasiñska., Marta Ilona Wojtyoe., El¿bieta K., Jagusztyn Krynicka. (2020): Helicobacter pylori treatment in the post-antibiotics era – searching for new drug targets. Appl. Microbiol.104:9891–9905.
Poovendran P., Kalaigandhi V., Poongunran E., (2011): Antimicrobial activity of the leaves of Cocculus hirsutus against gastric ulcer producing Helicobacter pylori. J. Pharm. Res. 4, 4294–4295.
Preeti Pandey., Vijay Verma., Gunjan Gautam., Nilima Kumari., Suman Kumar Dhar., SamudralaGourinath., (2017): Targeting the -clamp in Helicobacter pylori with FDA-approved drugs reveals micromolar inhibition by diflunisal.
Preeti Pandey., Khaja Faisal Tarique., Mohit Mazumder., Syed Arif Abdul Rehman., Nilimakumari and SamudralaGourinath., (2016): Structural insight into - Clamp and its interaction with DNA Ligase in Helicobacter pylori.
Pulic I., Loconte V and Zanotti G., (2014): Structural characterization at the atomic level of a molecular nano machine: the state of the art of Helicobacter pylori flagellum organization. Am J BiochemBiotechnol 10, 143- 161.
Roberts F., Roberts C. W., Johnson, J. J., Kyle, D. E., Krell T., Coggins J. R., et al., Evidence for the shikimate pathway in apicomplexan parasites. Nature, 393, 801-805.
Roesler BM., Rabelo Gonçalves EMA., Zeitune JMR., (2014): Virulence factors of Helicobacter pylori: A review. Clin Med Insights Gastroenterol 7:9–17.
Rong Q., Xu M., Dong Q., Zhang Y., Li Y., Ye G., Zhao L., (2016): In vitro and in vivo bactericidal activity of Tinosporasagittata and its main effective component, palmatine, against porcine Helicobacter pylori. BMC Complement. Altern. Med. 16, 331.
Rossez Y., Wolfson EB., Holmes A., Gally DL and Holden NJ., (2015): Bacterial flagella: twist and stick, or dodge across the kingdoms. PLoSPathog 11, 1004483.
S. Subedi., K. Moonens., E. Romão., A. Lo G. Vandenbussche., J. Bugaytsova., S. Muyldermans., T. Borén., H. Remaut., (2014): Expression, purification and X-ray crystallographic analysis of the Helicobacter pylori blood group antigen-binding adhesin BabA. Acta Crystallogr. F Struct.Biol. Commun. 70, 1631–1635.
Samantha Flores Treviño., Soraya Mendoza Olazarán., Paola BocanegraIbarias., Héctor Jesús Maldonado Garza and Elvira Garza González., (2018): Helicobacter pylori drug resistance: therapy changes and challenges. Expert Review of Gastroenterology & Hepatology.
Sandra Salillas and Javier Sancho., (2020): Flavodoxins as Novel Therapeutic Targets against Helicobacter pylori and Other Gastric Pathogens. Int. J. Mol. Sci. 21, 1881.
Sandra Salillas., Miriam Alías., Valérie Michel., Alejandro Mahía., Ainhoa Lucía., Liliana Rodrigues., Jessica Bueno., Juan José GalanoFrutos., Hilde De Reuse., Adrián Velázquez Campoy., José Alberto Carrodeguas., Carlos Sostres., Javier Castillo., José Antonio Aínsa., María Dolores Díaz de-Villegas., ÁngelLanas., ElietteTouati., Javier Sancho., (2019): Design, Synthesis and Efficacy testing of nitroethylene and 7- nitrobenzoxadiazol-based flavodoxin inhibitors against Helicobacter pylori drug resistant clinical strains and in Helicobacter pylori infected mice.
Saravanakumar K., Chellia R., Hu X., Kathiresan K., Oh D-H., Wang M-H., (2019): Eradication of Helicobacter pylori through the inhibition of urease and peptide deformylase: Computational and biological studies, Microbial Pathogenesis.
Sebastian Suerbaum M.D., and Pierre Michetti M.D., (2002): Helicobacter pylori infection. N Engl J Med, Vol. 347, No.15.
Shahani S., Monsef Esfahani H.R., Saeidnia S., Saniee P., Siavoshi F., Foroumadi A., Samadi N., Gohari A.R., (2012): Anti-Helicobacter pylori activity of the methanolic extract of Geumiranicum and its main compounds. Z. Naturforsch. C J. Biosci. 67, 172–180.
Štefaniæ Z., Mikleuševiæ G., Luiæ M., Bzowska A., LešèiæAšler I., (2017): Structural characterization of purine nucleoside phosphorylase from human pathogen Helicobacter pylori. Int J Biol Macromol 101:518 526.
Sycuro L. K., Pincus Z., Gutierrez K. D., Biboy J., Stern C. A., Vollmer W., and Salama N. R., (2010): Peptidoglycan cross linking relaxation promotes Helicobacter pylori’s helical shape and stomach colonization. Cell 141, 822– 833.
Tegtmeyer N., Wessler S., Necchi V., Rohde M., Harrer A., Rau T. T., Asche C. I., Boehm M., Loessner H., Figueiredo C., Naumann M., Palmisano R., Solcia E., Ricci V., and Backert S., (2017): Helicobacter pylori Employs a Unique Basolateral Type IV Secretion Mechanism for CagA Delivery. Cell Host Microbe 22, 552-560.e555.
Thomas DR., Francis NR., Xu C and De Rosier DJ., (2006): The three-dimensional structure of the flagellar rotor from a clockwise locked mutant of Salmonella typhimurium. J Bacteriol 188, 7039–7048.
Tibrewal N., Elliott GI., (2011): Evaluation of hadacidin analogues. Bioorganic Med Chem Lett 21:517–519. 67. Tomb JF., White O., Kerlavage AR., et al., (1997): The complete genome sequence of the gastric pathogen Helicobacter pylori. Nature 388:539-47
Valentina Loconte., Ivana Kekez., Dubravka Matkoviæalogoviæ and Giuseppe Zanotti., (2017): Structural characterization of FlgE2 protein from Helicobacter pylori hook. The FEBS Journal 4328–4342 2017.
Vidhi Mishra and Donald R. Ronning., (2012): Crystal Structures of the Helicobacter pylori MTAN Enzyme Reveal Specific Interactions between S Adenosylhomocysteine and the 52 -Alkylthio Binding Subsite. Biochemistry 51, 9763"9772.
Winans S. C., Burns D. L., and Christie P. J., (1996): Adaptation of a conjugal transfer system for the export of pathogenic macromolecules. Trends Microbiol. 4, 64– 68.
Winter J., Letley D., Rhead J., Atherton J., Robinson K., (2014): Helicobacter pylori membrane vesicles stimulate innate pro and anti-inflammatory responses and induce apoptosis in Jurkat T cells. Infect Immun 82:1372–1381.
Y. Y. Fei., A. Schmidt., G. Bylund., D. X. Johansson., S. Henriksson., C. Lebrilla., J. V. Solnick., T. Borén., X. D. Zhu., (2011): Use of real-time, label-free analysis in revealing low-affinity binding to blood group antigens by Helicobacter pylori. Anal. Chem. 83, 6336–6341.
Y.-C. Lee, T. H.-H. Chen H.M. Chiu et al., (2013): “benefit of mass eradication of Helicobacter pylori infection: a community-based study of gastric cancer prevention, “Gut, vol.62, no.5, pp.676–682
Yin Z. et al., (2014): DNA replication is the target for the antibacterial effects of nonsteroidal anti inflammatory drugs. Chem Biol 21, 481–487.
Yung Jun Ahn., Hye Jin Yoon., Byung Il Lee and Se Won Suh., (2004): Crystal Structure of Chorismate Synthase: A Novel FMN-binding Protein Fold and Functional Insights. J. Mol. Biol. 336, 903–915
Zagari RM., Rabitti S., Eusebi LH., et al., (2018): Treatment of Helicobacter pylori infection: A clinical practice update. Eur J Clin Invest. Jan; 48(1).
Zhemin Zhang., Qi Huang., Xuan Tao., Guobing Song., Peng Zheng., Hongyan Li., Hongzhe Sun and Wei Xia., (2019): The unique trimeric assembly of the virulence factor HtrA from Helicobacter pylorioccurs via Nterminal domain swapping. J. Biol. Chem. 119.007387.
Zhongming Ge., Diane E. Taylor., (1999): Contributions of Genome Sequencing to Understanding the Biology of Helicobacter pylori. Annu. Rev. Microbiol. 53:353–87.
Zhu P et al., (2017): Helicobacter pylori VacA induces autophagic cell death in gastric epithelial cells via the endoplasmic reticulum stress pathway. Cell Death Dis 8:3207.
