Abstract
BackgroundNodulisporic acids (NAs) are indole diterpene fungal metabolites exhibiting potent systemic efficacy against blood-feeding arthropods, e.g., bedbugs, fleas and ticks, via binding to arthropod specific glutamate-gated chloride channels. Intensive medicinal chemistry efforts employing a nodulisporic acid A template have led to the development of N-tert-butyl nodulisporamide as a product candidate for a once monthly treatment of fleas and ticks on companion animals. The source of the NAs is a monophyletic lineage of asexual endophytic fungal strains that is widely distributed in the tropics, tentatively identified as a Nodulisporium species and hypothesized to be the asexual state of a Hypoxylon species.Methods and ResultsInferences from GenBank sequences indicated that multiple researchers have encountered similar Nodulisporium endophytes in tropical plants and in air samples. Ascomata-derived cultures from a wood-inhabiting fungus, from Martinique and closely resembling Hypoxylon investiens, belonged to the same monophyletic clade as the NAs-producing endophytes. The hypothesis that the Martinique Hypoxylon collections were the sexual state of the NAs-producing endophytes was tested by mass spectrometric analysis of NAs, multi-gene phylogenetic analysis, and phenotypic comparisons of the conidial states. We established that the Martinique Hypoxylon strains produced an ample spectrum of NAs and were conspecific with the pantropical Nodulisporium endophytes, yet were distinct from H. investiens. A new species, H. pulicicidum, is proposed to accommodate this widespread organism.Conclusions and SignificanceKnowledge of the life cycle of H. pulicicidum will facilitate an understanding of the role of insecticidal compounds produced by the fungus, the significance of its infections in living plants and how it colonizes dead wood. The case of H. pulicicidum exemplifies how life cycle studies can consolidate disparate observations of a fungal organism, whether from environmental sequences, vegetative mycelia or field specimens, resulting in holistic species concepts critical to the assessment of the dimensions of fungal diversity.
Highlights
Arthropod ectoparasites can cause skin diseases and vector infectious pathogens
Knowledge of the life cycle of H. pulicicidum will facilitate an understanding of the role of insecticidal compounds produced by the fungus, the significance of its infections in living plants and how it colonizes dead wood
Nodulisporic acids (NAs) A was about 10fold more potent than ivermectin in a dog flea (Ctenocephalides canis) model [5,8]. This family of compounds became the focus of a major medicinal chemistry development program directed at long-acting oral cidal agents for control blood-sucking ectoparasites of companion animals [5,7,9]
Summary
Arthropod ectoparasites can cause skin diseases and vector infectious pathogens. In dogs and cats, fleas are the most important ectoparasites worldwide, especially the ubiquitous cat flea (Ctenocephalides felis). In the blowfly and mosquito assays, nodulisporic acid A (NA A, Fig. 1) was more potent than paraherquamide and abamectin, but less potent than ivermectin [1,5] Their systemic ectoparasiticide activity was discovered in a bedbug (Cimex lecularius) mouse assay [6,7]. NA A was about 10fold more potent than ivermectin in a dog flea (Ctenocephalides canis) model [5,8] As a result, this family of compounds became the focus of a major medicinal chemistry development program directed at long-acting oral cidal agents for control blood-sucking ectoparasites of companion animals [5,7,9]. Nodulisporic acids (NAs) are indole diterpene fungal metabolites exhibiting potent systemic efficacy against blood-feeding arthropods, e.g., bedbugs, fleas and ticks, via binding to arthropod specific glutamate-gated chloride channels. The source of the NAs is a monophyletic lineage of asexual endophytic fungal strains that is widely distributed in the tropics, tentatively identified as a Nodulisporium species and hypothesized to be the asexual state of a Hypoxylon species
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