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1.
J Ind Microbiol Biotechnol ; 50(1)2023 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-38052426

RESUMO

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 SUMMARY: Natural 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.


Assuntos
Antineoplásicos , Produtos Biológicos , Produtos Biológicos/química , Biblioteca Gênica , Fungos/genética , Indústria Farmacêutica
2.
Cell Chem Biol ; 23(11): 1383-1394, 2016 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-27746129

RESUMO

Natural products are invaluable historic sources of drugs for infectious diseases; however, the discovery of novel antimicrobial chemical scaffolds has waned in recent years. Concurrently, there is a pressing need for improved therapeutics to treat fungal infections. We employed a co-culture screen to identify ibomycin, a large polyketide macrolactone that has preferential killing activity against Cryptococcus neoformans. Using chemical and genome methods, we determined the structure of ibomycin and identified the biosynthetic cluster responsible for its synthesis. Chemogenomic profiling coupled with cell biological assays link ibomycin bioactivity to membrane function. The preferential activity of ibomycin toward C. neoformans is due to the ability of the compound to selectively permeate its cell wall. These results delineate a novel antifungal agent that is produced by one of the largest documented biosynthetic clusters to date and underscore the fact that there remains significant untapped chemical diversity of natural products with application in antimicrobial research.


Assuntos
Antifúngicos/química , Antifúngicos/farmacologia , Criptococose/tratamento farmacológico , Cryptococcus neoformans/efeitos dos fármacos , Lactonas/química , Lactonas/farmacologia , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Parede Celular/efeitos dos fármacos , Parede Celular/metabolismo , Técnicas de Cocultura , Criptococose/microbiologia , Cryptococcus neoformans/crescimento & desenvolvimento , Cryptococcus neoformans/metabolismo , Descoberta de Drogas , Fungos/efeitos dos fármacos , Fungos/crescimento & desenvolvimento , Fungos/metabolismo , Humanos , Testes de Sensibilidade Microbiana , Micoses/tratamento farmacológico , Micoses/microbiologia
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