Lipoprotein biosynthesis as a target for anti-Wolbachia treatment of filarial nematodes

Article English OPEN
Johnston, Kelly L ; Wu, Bo ; Guimarães, Ana ; Ford, Louise ; Slatko, Barton E ; Taylor, Mark J (2010)
  • Publisher: BioMed Central
  • Journal: Parasites & Vectors, volume 3, pages 99-99 (issn: 1756-3305, eissn: 1756-3305)
  • Related identifiers: doi: 10.1186/1756-3305-3-99, pmc: PMC2964653
  • Subject: wc_880 | RC109-216 | qx_203 | Infectious Diseases | Infectious and parasitic diseases | wc_885 | Research | Parasitology
    mesheuropmc: lipids (amino acids, peptides, and proteins) | parasitic diseases

<p>Abstract</p> <p>Background</p> <p>Lymphatic filariasis and onchocerciasis are debilitating diseases caused by filarial nematodes. Disease pathogenesis is induced by inflammatory responses following the death of the parasite. <it>Wolbachia </it>endosymbionts of filariae are potent inducers of innate and adaptive inflammation and bacterial lipoproteins have been identified as the ligands that bind toll-like receptors (TLR) 2 and TLR6. Lipoproteins are important structural and functional components of bacteria and therefore enzymes involved in <it>Wolbachia </it>lipoprotein biosynthesis are potential chemotherapeutic targets.</p> <p>Results</p> <p>Globomycin, a signal peptidase II (LspA) inhibitor, has activity against Gram-negative bacteria and a putative <it>lspA </it>gene has been identified from the <it>Wolbachia </it>genome of <it>Brugia malayi </it>(<it>w</it>Bm). The amino acids required for function are strictly conserved and functionality was verified by complementation tests in a temperature-sensitive <it>Escherichia coli lspA </it>mutant. Also, transformation of wild type <it>E. coli </it>with <it>Wolbachia lspA </it>conferred significant globomycin resistance. A cell-based screen has been developed utilizing a <it>Wolbachia</it>-containing <it>Aedes albopictus </it>cell line to assay novel compounds active against <it>Wolbachia</it>. Globomycin was screened using this assay, which resulted in a dose-dependent reduction in <it>Wolbachia </it>load. Furthermore, globomycin was also effective in reducing the motility and viability of adult <it>B. malayi in vitro</it>.</p> <p>Conclusions</p> <p>These studies validate lipoprotein biosynthesis as a target in an organism for which no genetic tools are available. Further studies to evaluate drugs targeting this pathway are underway as part of the A-WOL drug discovery and development program.</p>
  • References (45)
    45 references, page 1 of 5

    1. Taylor MJ, Bandi C, Hoerauf A: Wolbachia bacterial endosymbionts of filarial nematodes. Adv Parasitol 2005, 60:245-284.

    2. Debrah AY, Mand S, Marfo-Debrekyei Y, Batsa L, Pfarr K, Buttner M, Adjei O, Buttner D, Hoerauf A: Macrofilaricidal effect of 4 weeks of treatment with doxycycline on Wuchereria bancrofti. Trop Med Int Health 2007, 12:1433-1441.

    3. Debrah AY, Mand S, Marfo-Debrekyei Y, Batsa L, Pfarr K, Lawson B, Taylor M, Adjei O, Hoerauf A: Reduction in levels of plasma vascular endothelial growth factor-A and improvement in hydrocele patients by targeting endosymbiotic Wolbachia sp. in Wuchereria bancrofti with doxycycline. Am J Trop Med Hyg 2009, 80:956-963.

    4. Debrah AY, Mand S, Marfo-Debrekyei Y, Larbi J, Adjei O, Hoerauf A: Assessment of microfilarial loads in the skin of onchocerciasis patients after treatment with different regimens of doxycycline plus ivermectin. Filaria J 2006, 5:1.

    5. Debrah AY, Mand S, Specht S, Marfo-Debrekyei Y, Batsa L, Pfarr K, Larbi J, Lawson B, Taylor M, Adjei O, Hoerauf A: Doxycycline reduces plasma VEGF-C/sVEGFR-3 and improves pathology in lymphatic filariasis. PLoS Pathog 2006, 2:e92.

    6. Hoerauf A, Mand S, Fischer K, Kruppa T, Marfo-Debrekyei Y, Debrah AY, Pfarr KM, Adjei O, Buttner DW: Doxycycline as a novel strategy against bancroftian filariasis-depletion of Wolbachia endosymbionts from Wuchereria bancrofti and stop of microfilaria production. Med Microbiol Immunol 2003, 192:211-216.

    7. Hoerauf A, Mand S, Volkmann L, Buttner M, Marfo-Debrekyei Y, Taylor M, Adjei O, Buttner DW: Doxycycline in the treatment of human onchocerciasis: Kinetics of Wolbachia endobacteria reduction and of inhibition of embryogenesis in female Onchocerca worms. Microbes Infect 2003, 5:261-273.

    8. Hoerauf A, Specht S, Buttner M, Pfarr K, Mand S, Fimmers R, MarfoDebrekyei Y, Konadu P, Debrah AY, Bandi C, et al: Wolbachia endobacteria depletion by doxycycline as antifilarial therapy has macrofilaricidal activity in onchocerciasis: a randomized placebo-controlled study. Med Microbiol Immunol 2008, 197:295-311.

    9. Hoerauf A, Specht S, Marfo-Debrekyei Y, Buttner M, Debrah AY, Mand S, Batsa L, Brattig N, Konadu P, Bandi C, et al: Efficacy of 5-week doxycycline treatment on adult Onchocerca volvulus. Parasitol Res 2009, 104:437-447.

    10. Mand S, Pfarr K, Sahoo PK, Satapathy AK, Specht S, Klarmann U, Debrah AY, Ravindran B, Hoerauf A: Macrofilaricidal activity and amelioration of lymphatic pathology in bancroftian filariasis after 3 weeks of doxycycline followed by single-dose diethylcarbamazine. Am J Trop Med Hyg 2009, 81:702-711.

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