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

Aya C Taki,Anson V Koehler,Sylvia Urban,Andreas Hofmann,Guangxu Ma,Abdul Jabbar,Bill C H Chang,Tao Wang,Robert Brkljača,Jill Danne,Robin B Gasser,Sarah Ellis

doi:10.3390/pathogens9070550

Abstract

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.

Highlights

Parasitic helminths cause substantial morbidity and mortality in human and animals.The World Health Organization (WHO) estimates that more than 1.5 billion people (24% of the world’s population) are infected with soil-transmitted helminths worldwide [1]
The control of H. contortus and related nematodes relies on the use of a limited number of anti-parasitic drugs and their excessive and often uncontrolled use has led to widespread resistance in these worms against these drugs [7,8], even to those most-recently introduced into the commercial market [9,10,11]
We explored the activity of select secondary metabolites against H. contortus using established in vitro methods, with the aim of identifying candidate compounds to optimise and develop as anthelmintic drugs

Summary

Introduction

Parasitic helminths (worms) cause substantial morbidity and mortality in human and animals.The World Health Organization (WHO) estimates that more than 1.5 billion people (24% of the world’s population) are infected with soil-transmitted helminths worldwide [1]. The barber’s pole worm, Haemonchus contortus (order Strongylida) is a highly pathogenic nematode, primarily of ruminants, and has a global distribution [3]. This blood-feeding worm causes anaemia, associated complications and death in severely affected animals [4] and major productivity and economic losses to farmers and livestock industries [5,6]. The control of H. contortus and related nematodes relies on the use of a limited number of anti-parasitic drugs and their excessive and often uncontrolled use has led to widespread resistance in these worms against these drugs (within as few as two years) [7,8], even to those most-recently introduced into the commercial market (e.g., monepantel) [9,10,11]. The relatively rapid emergence (within 5–10 years) of resistance in gastrointestinal nematode populations [7] means that there is a continued need for the discovery of new compounds with modes/mechanisms of action which are distinct from those presently available on the commercial market [12,13]

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Conclusion