An Ivermectin-Sensitive Glutamate-Gated Chloride Channel from the Parasitic Nematode Haemonchus contortus

ABSTRACT The phase II detoxification system glutathione transferase (GST) is associated with the establishment of parasitic nematode infections within the gastrointestinal environment of the mammalian host. We report the functional analysis of a GST from an important worldwide parasitic nematode of small ruminants, Haemonchus contortus. This GST shows limited activity with a range of classical GST substrates but effectively binds hematin. The high-affinity binding site for hematin was not present in the GST showing the most identity, CE07055 from the free-living nematode Caenorhabditis elegans. This finding suggests that the high-affinity binding of hematin may represent a parasite adaptation to blood or tissue feeding from the host.

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Natural Compounds from the Marine Brown Alga Caulocystis cephalornithos with Potent In Vitro-Activity against the Parasitic Nematode Haemonchus contortus

Pathogens ◽

10.3390/pathogens9070550 ◽

2020 ◽

Vol 9 (7) ◽

pp. 550

Author(s):

Aya C. Taki ◽

Robert Brkljača ◽

Tao Wang ◽

Anson V. Koehler ◽

Guangxu Ma ◽

...

Keyword(s):

Haemonchus Contortus ◽

Brown Alga ◽

Parasitic Nematode ◽

Anthelmintic Activity ◽

Adult Males ◽

Terrestrial Plants ◽

Third Stage ◽

Future Work ◽

Marine Brown Alga

Eight secondary metabolites (1 to 8) were isolated from a marine sponge, a marine alga and three terrestrial plants collected in Australia and subsequently chemically characterised. Here, these natural product-derived compounds were screened for in vitro-anthelmintic activity against the larvae and adult stages of Haemonchus contortus (barber’s pole worm)—a highly pathogenic parasitic nematode of ruminants. Using an optimised, whole-organism screening system, compounds were tested on exsheathed third-stage larvae (xL3s) and fourth-stage larvae (L4s). Anthelmintic activity was initially evaluated on these stages based on the inhibition of motility, development and/or changes in morphology (phenotype). We identified two compounds, 6-undecylsalicylic acid (3) and 6-tridecylsalicylic acid (4) isolated from the marine brown alga, Caulocystis cephalornithos, with inhibitory effects on xL3 and L4 motility and larval development, and the induction of a “skinny-straight” phenotype. Subsequent testing showed that these two compounds had an acute nematocidal effect (within 1–12 h) on adult males and females of H. contortus. Ultrastructural analysis of adult worms treated with compound 4 revealed significant damage to subcuticular musculature and associated tissues and cellular organelles including mitochondria. In conclusion, the present study has discovered two algal compounds possessing acute anthelmintic effects and with potential for hit-to-lead progression. Future work should focus on undertaking a structure-activity relationship study and on elucidating the mode(s) of action of optimised compounds.

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An ion-sensitive microelectrode study on the effect of a high concentration of ivermectin on chloride balance in the somatic muscle bag cells of Ascaris suum

Parasitology ◽

10.1017/s0031182000067172 ◽

1993 ◽

Vol 106 (4) ◽

pp. 421-427 ◽

Cited By ~ 4

Author(s):

H. R. Parri ◽

M. B. A. Djamgoz ◽

L. Holden-Dye ◽

R. J. Walker

Keyword(s):

Receptor Antagonist ◽

Chloride Channel ◽

Gaba Receptor ◽

Parasitic Nematode ◽

Ascaris Suum ◽

Muscle Cells ◽

High Concentration ◽

Somatic Muscle ◽

Ion Sensitive Microelectrodes ◽

Bag Cells

SUMMARYIvermectin has been shown to increase chloride conductances of invertebrate cells. On the muscle cells of the parasitic nematode Ascaris, ivermectin acts as both a GABA receptor antagonist and a chloride channel opener. In this study, ion-sensitive microelectrodes were used to investigate the effect of ivermectin on intracellular C1− concentration of the somatic muscle bag cells of Ascaris suum. Incubation of muscle cells with ivermectin (10 μM in 1% dimethyl sulphoxide vehicle for 60 min) increased intracellular C1− by 2·9 mM or 15% compared to controls (P > 0·01, n = 6).

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It Takes Two: Dimerization Is Essential for the Broad-Spectrum Predatory and Defensive Activities of the Venom Peptide Mp1a from the Jack Jumper Ant Myrmecia pilosula

Biomedicines ◽

10.3390/biomedicines8070185 ◽

2020 ◽

Vol 8 (7) ◽

pp. 185 ◽

Cited By ~ 2

Author(s):

Samantha A. Nixon ◽

Zoltan Dekan ◽

Samuel D. Robinson ◽

Shaodong Guo ◽

Irina Vetter ◽

...

Keyword(s):

Broad Spectrum ◽

Haemonchus Contortus ◽

Parasitic Nematode ◽

Biological Activities ◽

Fruit Fly ◽

Cell Types ◽

Activity Data ◽

Chemical Complexity ◽

Rational Engineering ◽

Structure Activity

Ant venoms have recently attracted increased attention due to their chemical complexity, novel molecular frameworks, and diverse biological activities. The heterodimeric peptide ∆-myrtoxin-Mp1a (Mp1a) from the venom of the Australian jack jumper ant, Myrmecia pilosula, exhibits antimicrobial, membrane-disrupting, and pain-inducing activities. In the present study, we examined the activity of Mp1a and a panel of synthetic analogues against the gastrointestinal parasitic nematode Haemonchus contortus, the fruit fly Drosophila melanogaster, and for their ability to stimulate pain-sensing neurons. Mp1a was found to be both insecticidal and anthelmintic, and it robustly activated mammalian sensory neurons at concentrations similar to those reported to elicit antimicrobial and cytotoxic activity. The native antiparallel Mp1a heterodimer was more potent than heterodimers with alternative disulfide connectivity, as well as monomeric analogues. We conclude that the membrane-disrupting effects of Mp1a confer broad-spectrum biological activities that facilitate both predation and defense for the ant. Our structure–activity data also provide a foundation for the rational engineering of analogues with selectivity for particular cell types.

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