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Biswas , R. K. (1) ; Ehlers, M. M. (1,2) ; Kock M. (1,2)

Identification of metronidazole resistance pathway proteins in Trichomonas vaginalis. Biswas , R. K. (1) ; Ehlers, M. M. (1,2) ; Kock M. (1,2) (1) Department of Medical Microbiology, University of Pretoria, Pretoria, South Africa

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Biswas , R. K. (1) ; Ehlers, M. M. (1,2) ; Kock M. (1,2)

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  1. Identification of metronidazole resistance pathway proteins in Trichomonas vaginalis Biswas, R. K.(1); Ehlers, M. M. (1,2) ; Kock M.(1,2) (1) Department of Medical Microbiology, University of Pretoria, Pretoria, South Africa (2) Department of Medical Microbiology, Tshwane Academic Division, National Health Laboratory Service, South Africa

  2. Trichomoniasis • Trichomoniasis caused by Trichomonasvaginalis • Vaginitis, urethritis, and prostatitis • Adverse pregnancy outcomes • Male and female infertility • Pelvic inflammatory states • Increase risk of HIV-1 • Prevalence • ≥ 75% of commercial sex workers • ≥ 5% of women attending family planning clinics • ≥ 32% of women attending STD clinics • ≥ 25% of women attending gynaecology clinics

  3. Trichomoniasis • 5-nitroimidazoles or metronidazole • Prodrug  Active Drug (Reduction of Metronidazole) • Hydrogenosome enzymes (mitochondria-like organelles produces molecular hydrogen and synthesize ATP through substrate-level phosphorylation) • Oxidative decarboxylation of pyruvate by Pyruvate:Ferridoxin Oxidoreductase (PFOR) and Ferridoxin • Development of resistance • Decreased drug uptake or increased efflux • Decreased drug activation/change in the biological target • Increased oxygen scavenging capabilities (SOD/peroxidase) • Enhanced activity of DNA repair enzymes

  4. Trichomonas genome and metronidazole driven gene expression • ~160MB Genome, 59 672 protein-coding genes (only 65% of which contain introns) • 1136 RNA-coding genes (668 rRNA and 438 tRNA) • Highly repetitive genome segments • 38 201 ‘repeat genes’ (protein-coding genes present in high copy number-paralouges) • PFOR (iron-sulfur cluster binding domain) • Hydrogenase • Lactate dehydrogenase • NADH-ferridoxin • Malate dehydrogenase • Malic enzymes • Pyruvate kinase • SCS • HDH • NADH:FOR • Flavin reductase • Alcohol dehydrogenase Hydrogenosomal proteins are also associated with virulence

  5. Multiple paralogs of Hydragenosomal genes • Why does a protozoan parasite keep such a large set of paralouges??? • Are they redundant – pseudo genes??? • if YES – Why ??? if NO • Conditionally expressed ??? • Is there any crosstalk between these genes/paralouges ??? • Their role in drug resistance???

  6. Probing multiple paralogs • Multiple paralouges were retrieved from genome database • Computation of overrepresented Motif • Motif analysis – protein family • Protein family interaction • Analysis of protein interaction – Hydrogenosomal proteins

  7. Over represented protein domains/motifs ATP-grasp_2 SCS 4Fe-4S binding domain PFOR ME Malic enzyme, N-terminal domain Pyruvate kinase, barrel domain Pyruvate kinase Motifs/family Proteins

  8. Over represented protein domains/motifs Hydrogenase 4Fe-4S dicluster domain lactate/malate dehydrogenase, NAD binding domain HDH lactate/malate dehydrogenase, NAD binding domain LDH Motifs/family Proteins

  9. Interactions PFOR Pyruvate kinase

  10. Interactions Hydrogenase No significant interaction

  11. Interactions L / MDH

  12. Conclusion Hydrogenosomal enzymes (MDH and LDH) UP or Down regulated respectively in response to Metronidazole MDH and LDH share similar NAD binding domain and likely to interact Hydrogenase/Pyruvate kinase interaction Future prospects Analysis of interacting proteins and their expression profiles influenced by Metronidazole Analysis of other proteins whose expression was found to be up or down regulated influenced by Metronidazole Expression profile of T. vaginalis (Transcriptomics profile)

  13. Lets discuss to get rid of itch Thank you for your kind Attention!!!

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