Drug discovery from natural products

Natural product compounds are the source of numerous therapeutic agents. Recent progress to discover drugs from natural product sources has resulted in compounds that are being developed to treat cancer, resistant bacteria and viruses and immunosuppressive disorders. Many of these compounds were discovered by applying recent advances in understanding the genetics of secondary metabolism in actinomycetes, exploring the marine environment and applying new screening technologies. In many instances, the discovery of a novel natural product serves as a tool to better understand targets and pathways in the disease process. This review describes recent progress in drug discovery from natural sources including several examples of compounds that inhibit novel drug targets.     

The soil metagenome--a rich resource for the discovery of novel natural products

Soil microorganisms have been the most valuable source of natural products, providing industrially important antibiotics and biocatalysts. But, of late, the discovery rate of novel biomolecules using traditional cultivation techniques has been extremely low, as most soil microorganisms cannot be cultured in this way. The development of novel cultivation-dependent and molecular cultivation-independent approaches has paved the way for a new era of product recovery from soil microorganisms. In particular, gene-mining based on the construction and screening of complex libraries derived from the soil metagenome provides opportunities to fully explore and exploit the enormous genetic and metabolic diversity of soil microorganisms. This strategy has already resulted in the isolation of novel biocatalysts and bioactive molecules.     

Bioactive natural products from marine cyanobacteria for drug discovery

The prokaryotic marine cyanobacteria continue to be an important source of structurally bioactive secondary metabolites. A majority of these molecules are nitrogen-containing compounds biosynthesized by large multimodular nonribosomal polypeptide (NRP) or mixed polyketide-NRP enzymatic systems. A total of 128 marine cyanobacterial alkaloids, published in the literature between January 2001 and December 2006, are presented in this review with emphasis on their biosynthesis and biological activities. In addition, a number of highly cytotoxic compounds such as hectochlorin, lyngbyabellins, apratoxins, and aurilides have been identified as potential lead compounds for the development of anticancer agents. A brief coverage on the distribution of natural product biosynthetic genes as well as the mechanisms of tailoring enzymes involved in the biosynthesis of cyanobacterial compounds will also be given.     

Genome-guided discovery of diverse natural products from Burkholderia sp.

Burkholderia species have emerged as a new source of diverse natural products. This mini-review covers all of the natural products discovered in recent years from Burkholderia sp. by genome-guided approaches—these refer to the use of bacterial genome sequence as an entry point for in silico structural prediction, wet lab experimental design, and execution. While reliable structural prediction based on cryptic biosynthetic gene cluster sequence was not always possible due to noncanonical domains and/or module organization of a deduced biosynthetic pathway, a molecular genetic method was often employed to detect or alter the expression level of the gene cluster to achieve an observable phenotype, which facilitated downstream natural product purification and identification. Those examples of natural product discovery from Burkholderia sp. provide practical guidance for future exploration of Gram-negative bacteria as a new source of natural products.     

Preparative chromatography and natural products discovery

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Diversifying microbial natural products for drug discovery

Historically, nature has provided the source for the majority of the drugs in use today. More than 20,000 microbial secondary metabolites have been described, but only a small percentage of these have been carried forward as natural product drugs. Natural products are in tough competition with large chemical libraries and with combinatorial chemistries. Hence, each step of a natural product program has to be more efficient than ever, starting from the collection of environmental samples and the selection of strains, to metabolic expression, genetic exploitation, sample preparation and chemical dereplication. This review will focus on approaches for diversifying microbial natural product strains and extract libraries, while decreasing genetic and chemical redundancy.V. Knight and J.-J. Sanglier contributed equally to this work     

New aspects of natural products in drug discovery

During the past 15 years, most large pharmaceutical companies have decreased the screening of natural products for drug discovery in favor of synthetic compound libraries. Main reasons for this include the incompatibility of natural product libraries with high-throughput screening and the marginal improvement in core technologies for natural product screening in the late 1980s and early 1990 s. Recently, the development of new technologies has revolutionized the screening of natural products. Applying these technologies compensates for the inherent limitations of natural products and offers a unique opportunity to re-establish natural products as a major source for drug discovery. Examples of these new advances and technologies are described in this review.     

Unlocking the potential of natural products in drug discovery

The natural product specialized metabolites produced by microbes and plants are the backbone of our current drugs. Despite their historical importance, few pharmaceutical companies currently emphasize their exploitation in new drug discovery and instead favour synthetic compounds as more tractable alternatives. Ironically, we are in a Golden Age of understanding of natural product biosynthesis, biochemistry and engineering. These advances have the potential to usher in a new era of natural product exploration and development taking full advantage of the unique and favourable properties of natural products compounds in drug discovery.     

The impact of natural products upon modern drug discovery

In the period 1970-2006, a total of 24 unique natural products were discovered that led to an approved drug. We analyze these successful leads in terms of drug-like properties, and show that they can be divided into two equal subsets. The first falls in the 'Lipinski universe' and complies with the Rule of Five. The second is a 'parallel universe' that violates the rules. Nevertheless, the latter compounds remain largely compliant in terms of logP and H-bond donors, highlighting the importance of these two metrics in predicting bioavailability. Natural products are often cited as an exception to Lipinski's rules. We believe this is because nature has learned to maintain low hydrophobicity and intermolecular H-bond donating potential when it needs to make biologically active compounds with high molecular weight and large numbers of rotatable bonds. In addition, natural products are more likely than purely synthetic compounds to resemble biosynthetic intermediates or endogenous metabolites, and hence take advantage of active transport mechanisms. Interestingly, the natural product leads in the Lipinski and parallel universe had an identical success rate (50%) in delivering an oral drug.     

Sequencing effort dictates gene discovery in marine microbial metagenomes

Massive metagenomic sequencing combined with gene prediction methods were previously used to compile the gene catalogue of the ocean and host-associated microbes. Global expeditions conducted over the past 15 years have sampled the ocean to build a catalogue of genes from pelagic microbes. Here we undertook a large sequencing effort of a perturbed Red Sea plankton community to uncover that the rate of gene discovery increases continuously with sequencing effort, with no indication that the retrieved 2.83 million non-redundant (complete) genes predicted from the experiment represented a nearly complete inventory of the genes present in the sampled community (i.e., no evidence of saturation). The underlying reason is the Pareto-like distribution of the abundance of genes in the plankton community, resulting in a very long tail of millions of genes present at remarkably low abundances, which can only be retrieved through massive sequencing. Microbial metagenomic projects retrieve a variable number of unique genes per Tera base-pair (Tbp), with a median value of 14.7 million unique genes per Tbp sequenced across projects. The increase in the rate of gene discovery in microbial metagenomes with sequencing effort implies that there is ample room for new gene discovery in further ocean and holobiont sequencing studies.     

The re-emerging role of microbial natural products in antibiotic discovery

New classes of antibacterial compounds are urgently needed to respond to the high frequency of occurrence of resistances to all major classes of known antibiotics. Microbial natural products have been for decades one of the most successful sources of drugs to treat infectious diseases but today, the emerging unmet clinical need poses completely new challenges to the discovery of novel candidates with the desired properties to be developed as antibiotics. While natural products discovery programs have been gradually abandoned by the big pharma, smaller biotechnology companies and research organizations are taking over the lead in the discovery of novel antibacterials. Recent years have seen new approaches and technologies being developed and integrated in a multidisciplinary effort to further exploit microbial resources and their biosynthetic potential as an untapped source of novel molecules. New strategies to isolate novel species thought to be uncultivable, and synthetic biology approaches ranging from genome mining of microbial strains for cryptic biosynthetic pathways to their heterologous expression have been emerging in combination with high throughput sequencing platforms, integrated bioinformatic analysis, and on-site analytical detection and dereplication tools for novel compounds. These different innovative approaches are defining a completely new framework that is setting the bases for the future discovery of novel chemical scaffolds that should foster a renewed interest in the identification of novel classes of natural product antibiotics from the microbial world.     

Genomics-enabled discovery of phosphonate natural products and their biosynthetic pathways

Phosphonate natural products have proven to be a rich source of useful pharmaceutical, agricultural, and biotechnology products, whereas study of their biosynthetic pathways has revealed numerous intriguing enzymes that catalyze unprecedented biochemistry. Here we review the history of phosphonate natural product discovery, highlighting technological advances that have played a key role in the recent advances in their discovery. Central to these developments has been the application of genomics, which allowed discovery and development of a global phosphonate metabolic framework to guide research efforts. This framework suggests that the future of phosphonate natural products remains bright, with many new compounds and pathways yet to be discovered.     

Recombinant environmental libraries provide access to microbial diversity for drug discovery from natural products

To further explore possible avenues for accessing microbial biodiversity for drug discovery from natural products, we constructed and screened a 5,000-clone "shotgun" environmental DNA library by using an Escherichia coli-Streptomyces lividans shuttle cosmid vector and DNA inserts from microbes derived directly (without cultivation) from soil. The library was analyzed by several means to assess diversity, genetic content, and expression of heterologous genes in both expression hosts. We found that the phylogenetic content of the DNA library was extremely diverse, representing mostly microorganisms that have not been described previously. The library was screened by PCR for sequences similar to parts of type I polyketide synthase genes and tested for the expression of new molecules by screening of live colonies and cell extracts. The results revealed new polyketide synthase genes in at least eight clones. In addition, at least five additional clones were confirmed by high-pressure liquid chromatography analysis and/or biological activity to produce heterologous molecules. These data reinforce the idea that exploiting previously unknown or uncultivated microorganisms for the discovery of novel natural products has potential value and, most importantly, suggest a strategy for developing this technology into a realistic and effective drug discovery tool.     

New natural products as new leads for antibacterial drug discovery

Natural products have been a rich source of antibacterial drugs for many decades, but investments in this area have declined over the past two decades. The purpose of this review article is to provide a recent survey of new natural product classes and the mechanisms by which they work.