Dataset Information

Mining for natural product antileishmanials in a fungal extract library.

ABSTRACT: Leishmaniasis is a Neglected Tropical Disease caused by the insect-vector borne protozoan parasite, Leishmania species. Infection affects millions of the World's poorest, however vaccines are absent and drug therapy limited. Recently, public-private partnerships have developed to identify new modes of controlling leishmaniasis. Most of these collaborative efforts have relied upon the small molecule synthetic compound libraries held by industry, but the number of New Chemical Entities (NCE) identified and entering development as antileishmanials has been very low. In light of this, here we describe a public-private effort to identify natural products with activity against Leishmania mexicana, a causative agent of cutaneous leishmanaisis (CL). Utilising Hypha Discovery's fungal extract library which is rich in small molecule (<500 molecular weight) secondary metabolites, we undertook an iterative phenotypic screening and fractionation approach to identify potent and selective antileishmanial hits. This led to the identification of a novel oxidised bisabolane sesquiterpene which demonstrated activity in an infected cell model and was shown to disrupt multiple processes using a metabolomic approach. In addition, and importantly, this study also sets a precedent for new approaches for CL drug discovery.

SUBMITTER: Mbekeani AJ

PROVIDER: S-EPMC6904819 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Mining for natural product antileishmanials in a fungal extract library.

Mbekeani A J AJ Jones R S RS Bassas Llorens M M Elliot J J Regnault C C Barrett M P MP Steele J J Kebede B B Wrigley S K SK Evans L L Denny P W PW

International journal for parasitology. Drugs and drug resistance 20190611

Leishmaniasis is a Neglected Tropical Disease caused by the insect-vector borne protozoan parasite, Leishmania species. Infection affects millions of the World's poorest, however vaccines are absent and drug therapy limited. Recently, public-private partnerships have developed to identify new modes of controlling leishmaniasis. Most of these collaborative efforts have relied upon the small molecule synthetic compound libraries held by industry, but the number of New Chemical Entities (NCE) ident ...[more]

PMID: 31208892

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Project description:Microbial natural products are specialized metabolites that are sources of many bioactive compounds including antibiotics, antifungals, antiparasitics, anticancer agents, and probes of biology. The assembly of libraries of producers of natural products has traditionally been the province of the pharmaceutical industry. This sector has gathered significant historical collections of bacteria and fungi to identify new drug leads with outstanding outcomes-upwards of 60% of drug scaffolds originate from such libraries. Despite this success, the repeated rediscovery of known compounds and the resultant diminishing chemical novelty contributed to a pivot from this source of bioactive compounds toward more tractable synthetic compounds in the drug industry. The advent of advanced mass spectrometry tools, along with rapid whole genome sequencing and in silico identification of biosynthetic gene clusters that encode the machinery necessary for the synthesis of specialized metabolites, offers the opportunity to revisit microbial natural product libraries with renewed vigor. Assembling a suitable library of microbes and extracts for screening requires the investment of resources and the development of methods that have customarily been the proprietary purview of large pharmaceutical companies. Here, we report a perspective on our efforts to assemble a library of natural product-producing microbes and the establishment of methods to extract and fractionate bioactive compounds using resources available to most academic labs. We validate the library and approach through a series of screens for antimicrobial and cytotoxic agents. This work serves as a blueprint for establishing libraries of microbial natural product producers and bioactive extract fractions suitable for screens of bioactive compounds.One-sentence summaryNatural products are key to discovery of novel antimicrobial agents: Here, we describe our experience and lessons learned in constructing a microbial natural product and pre-fractionated extract library.

Dataset Information

Mining for natural product antileishmanials in a fungal extract library.

Publications

Mining for natural product antileishmanials in a fungal extract library.

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