Omics based approach for biodiscovery of microbial natural products in antibiotic resistance era

The need for a new antibiotic pipeline to confront threat imposed by resistant pathogens has become a major global concern for human health. To confront the challenge there is a need for discovery and development of new class of antibiotics. Nature which is considered treasure trove, there is re-emerged interest in exploring untapped microbial to yield novel molecules, due to their wide array of negative effects associated with synthetic drugs. Natural product researchers have developed many new techniques over the past few years for developing diverse compounds of biopotential. Taking edge in the advancement of genomics, genetic engineering, in silico drug design, surface modification, scaffolds, pharmacophores and target-based approach is necessary. These techniques have been economically sustainable and also proven efficient in natural product discovery. This review will focus on recent advances in diverse discipline approach from integrated Bioinformatics predictions, genetic engineering and medicinal chemistry for the synthesis of natural products vital for the discovery of novel antibiotics having potential application.     

真菌来源的药用天然产物

天然产物及其衍生物,包括基于天然产物药效基团结构设计的化合物,约占临床药物的50%以上。几个世纪以来,真菌天然产物的药用价值闻名于世。无论从市场前景还是人道主义角度,真菌来源的小分子药物都具有极高的应用价值。本篇综述总结了真菌天然产物在临床上的应用,并以他汀类药物的研发历程揭示了真菌来源小分子是化学合成药物研发的重要灵感源泉。本篇综述涵盖了真菌来源的药物小分子,包括天然药物、相关衍生物以及结构修饰药物。     

Antimicrobial properties of Allium sativum (garlic)

Although garlic has been used for its medicinal properties for thousands of years, investigations into its mode of action are relatively recent. Garlic has a wide spectrum of actions; not only is it antibacterial, antiviral, antifungal and antiprotozoal, but it also has beneficial effects on the cardiovascular and immune systems. Resurgence in the use of natural herbal alternatives has brought the use of medicinal plants to the forefront of pharmacological investigations, and many new drugs are being discovered. This review aims to address the historical use of garlic and its sulfur chemistry, and to provide a basis for further research into its antimicrobial properties.     

海洋沉积物来源链霉菌属次生代谢产物及其生物活性研究进展

海洋沉积物是营养较为丰富的微生物栖息地,近年来从海洋沉积物中分离培养出了大量海洋链霉菌,从中还发现了一些新的属种。人们已从海洋沉积物来源链霉菌属中发现了许多具有药用价值的活性化合物,有力推动了海洋天然产物化学的发展,并为新药研发提供基础。本文就海洋沉积物来源链霉菌属次生代谢产物的结构类型及其生物活性进行简要综述。     

Solid phase synthesis of complex natural products and libraries thereof.

Natural products have served as an important source of medicinal compounds and pharmaceutical leads over the last century. Within the last 10 years, significant interest has developed in applying combinatorial chemistry techniques to the study of natural products and their biological activities. In this review, we examine several representative efforts wherein natural product skeletons have been constructed or immobilized on solid support and subsequently derivatized, giving rise to analog libraries useful in understanding the structure-activity relationships of the parent natural product. Issues such as target selection, library design, linker development, automation, and library characterization are addressed.     

氟化天然产物生物合成的研究进展

氟元素是一种具有特殊性质的卤素,含氟有机物可广泛应用于生物有机化学、药物化学和生物材料科学等领域.尽管C-F键的合成方法有所创新,但将氟元素掺入到结构复杂的生物活性分子中的方法较少,因此选择性的氟化仍极具挑战性.本文从自然界中氟化天然产物及氟化酶的发现、氟化天然产物的合成通路、氟化天然产物合成机制的意义、氟化酶的进化及...     

Natural products and combinatorial chemistry: back to the future

The introduction of high-throughput synthesis and combinatorial chemistry has precipitated a global decline in the screening of natural products by the pharmaceutical industry. Some companies terminated their natural products program, despite the unproven success of the new technologies. This was a premature decision, as natural products have a long history of providing important medicinal agents. Furthermore, they occupy a complementary region of chemical space compared with the typical synthetic compound library. For these reasons, the interest in natural products has been rekindled. Various approaches have evolved that combine the power of natural products and organic chemistry, ranging from the combinatorial total synthesis of analogues to the exploration of natural product scaffolds and the design of completely unnatural molecules that resemble natural products in their molecular characteristics.     

Natural product derived promising anti-MRSA drug leads: A review

Multi-drug resistant Staphylococcus aureus infections have created a critical need for the development of new classes of antibacterials. Discovery of new naturally derived antibacterial agents with new mechanism of action remains a high priority globally. Several of the available antibacterial agents like β-lactams, polyketides, phenylpropanoids, aminoglycosides, macrolides, glycopeptides, streptogramins and lipopeptides are natural products or their semisynthetic variations. In the current scenario of alarming rise in antibacterial resistance, revisiting natural products with modern chemistry and biology tools has fascinated many medicinal chemists for discovery and development of natural products or derived semisynthetic derivatives as effective antibacterial agents. This review underlines the structures and anti-MRSA activity of various natural product derivatives covering recent reports, in vivo activities and brief Structure Activity Relationships (SARs).     

Needs for new plant-derived pharmaceuticals in the post-genome era: an industrial view in drug research and development

Plant metabolites have been the successful source of drugs and provided considerable value not only to the pharmaceutical industry but also to human health problems. Although pharmaceutical companies significantly decreased their activities in natural product discovery during the past few decades, various multidisciplinary approaches have been made to create new opportunities for finding innovative plant derived pharmaceuticals in post-genome era. Strategies to integrate the knowledge on medicinal plants into rational drug screening, the unique biodiversity of plant metabolites into random drug screening, and the chemical diversity of plant metabolites into combinatorial chemistry have been reviewed with concrete examples. Innovative biotechnologies in plant cell and tissue cultures, and the latest achievements in metabolic engineering and genetic modification should significantly improve the production sustainability and efficiency of plant-derived pharmaceuticals.     

天然药物化学实验教学改革与思考

天然药物化学是药学专业一门重要的专业基础课程。近年来,天然药物在世界范围内受到广为重视与青睐,而随着国家中医药现代化步伐的加快,对创新型药学专业人才的培养也提出了迫切的要求,天然药物化学实验在教学中的重要性与日俱增。为了进一步提高天然药物化学实验课程的教学效果,使之紧密切合学科发展的前沿,笔者根据本教研室在实验教学实践中的相关经验,结合该课程的特点与定位,总结了天然药物化学实验教学过程中存在的问题,并对课程改革进行了探讨与思考,针对课程重视程度低、教学中环保和可持续发展理念缺失、教学方法和手段单一、实验评价考核体系不合理等问题,提出了完善课程设计、严密教学方案、改进课程内容、改革考核标准等具体改进方法及措施。     

Combinatorial biosynthesis for drug development

Combinatorial biosynthesis can refer to any strategy for the genetic engineering of natural product biosynthesis to obtain new molecules, including the use of genetics for medicinal chemistry. However, it also implies the possibility that large libraries of complex compounds might be produced to feed a modern high-throughput screening operation. This review focuses on the multi-modular enzymes that produce polyketides, nonribosomal peptides, and hybrid polyketide-peptide compounds, which are the enzymes that appear to be most amenable to truly combinatorial approaches. The recent establishment of a high-throughput strategy for testing the activity of many non-natural combinations of modules from these enzymes should help speed the advance of this technology.     

New Caledonia: A Hot Spot for Valuable Chemodiversity Part 3: Santalales,Caryophyllales, and Asterids

The flora of New Caledonia encompasses more than 3000 plant species and an endemism of almost 80%. New Caledonia is even considered as one of the 34 ‘hot spots’ for biodiversity. Considering the current global loss of biodiversity and the fact that several drugs and pesticides become obsolete, there is an urgent need to increase sampling and research on new natural products. In this context, here, we reviewed the chemical knowledge available on New Caledonian native flora from economical perspectives. We expect that a better knowledge of the economic potential of plant chemistry will encourage the plantation of native plants for the development of a sustainable economy which will participate in the conservation of biodiversity. This review is divided into three parts, and the third part which is presented here summarizes the scientific literature related to the chemistry of endemic santalales, caryophyllales, and asterids. We show that the high rate of endemism is correlated with the originality of phytochemicals encountered in New Caledonian plants. A total of 176 original natural compounds have been identified from these plants, whereas many species have not been investigated so far. We also discuss the economic potential of plants and molecules with consideration of their medicinal and industrial perspectives. This review finally highlights several groups, such as Sapotaceae, that are unexplored in New Caledonia despite the high chemical interest in them. These plants are considered to have priority in future chemical investigations.     

Natural products: A continuing source of novel drug leads

Background

Nature has been a source of medicinal products for millennia, with many useful drugs developed from plant sources. Following discovery of the penicillins, drug discovery from microbial sources occurred and diving techniques in the 1970s opened the seas. Combinatorial chemistry (late 1980s), shifted the focus of drug discovery efforts from Nature to the laboratory bench.

Scope of Review

This review traces natural products drug discovery, outlining important drugs from natural sources that revolutionized treatment of serious diseases. It is clear Nature will continue to be a major source of new structural leads, and effective drug development depends on multidisciplinary collaborations.

Major Conclusions

The explosion of genetic information led not only to novel screens, but the genetic techniques permitted the implementation of combinatorial biosynthetic technology and genome mining. The knowledge gained has allowed unknown molecules to be identified. These novel bioactive structures can be optimized by using combinatorial chemistry generating new drug candidates for many diseases.

General Significance

The advent of genetic techniques that permitted the isolation / expression of biosynthetic cassettes from microbes may well be the new frontier for natural products lead discovery. It is now apparent that biodiversity may be much greater in those organisms. The numbers of potential species involved in the microbial world are many orders of magnitude greater than those of plants and multi-celled animals. Coupling these numbers to the number of currently unexpressed biosynthetic clusters now identified (> 10 per species) the potential of microbial diversity remains essentially untapped.     

Antisense strategies

Antisense technology exploits oligonucleotide analogs to bind to target RNAs via Watson-Crick by hybridization. Once bound, the antisense agent either disables or induces the degradation of the target RNA. Antisense agents may also be used to alter splicing. Developing antisense technology involves the creation of a new pharmacology. The receptors, pre- and mRNAs, had never been studied before as sites for drug binding and action. The drugs, oligonucleotide analogs, had never made or tested as drugs before and no medicinal chemistry had been performed. The receptor binding mechanism, Watson-Crick hybridization had never been demonstrated as feasible to exploit from a pharmacological perspective. The post-receptor binding events were literally unknown and unexplored. During the past decade or more, substantial progress has been made in developing antisense pharmacology. A great deal has been learned about the basic mechanisms of antisense, the medicinal chemistry, the pharmacological, pharmacokinetic and toxicological properties of antisense molecules. Antisense technology has proven of great value in gene functionalization and target validation. With one drug marketed, Vitravene, and approximately 20 antisense drugs in clinical development, it appears that antisense drugs may prove of value in the treatment of a wide range of diseases. In this review, the progress is summarized, the limitations of the technology discussed and the future considered.     

Natural product derivatives with bactericidal activity against Gram-positive pathogens including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis

We have shown that the intentional engineering of a natural product biosynthesis pathway is a useful way to generate stereochemically complex scaffolds for use in the generation of combinatorial libraries that capture the structural features of both natural products and synthetic compounds. Analysis of a prototype library based upon nonactic acid lead to the discovery of triazole-containing nonactic acid analogs, a new structural class of antibiotic that exhibits bactericidal activity against drug resistant, Gram-positive pathogens including Staphylococcus aureus and Enterococcus faecalis.     

Click chemistry to probe Hsp90: Synthesis and evaluation of a series of triazole-containing novobiocin analogues

A series of triazole-containing novobiocin analogues has been designed, synthesized and their inhibitory activity determined. These compounds contain a triazole ring in lieu of the amide moiety present in the natural product. The anti-proliferative effects of these compounds were evaluated against two breast cancer cell lines (SKBr-3 and MCF-7), and manifested activities similar to their amide-containing counterparts. In addition, Hsp90-dependent client protein degradation was observed via Western blot analyses, supporting a common mode of Hsp90 inhibition for both structural classes.     

Exploring anti-TB leads from natural products library originated from marine microbes and medicinal plants

Multidrug-resistant tuberculosis (MDR-TB) and TB–HIV co-infection have become a great threat to global health. However, the last truly novel drug that was approved for the treatment of TB was discovered 40?years ago. The search for new effective drugs against TB has never been more intensive. Natural products derived from microbes and medicinal plants have been an important source of TB therapeutics. Recent advances have been made to accelerate the discovery rate of novel TB drugs including diversifying strategies for environmental strains, high-throughput screening (HTS) assays, and chemical diversity. This review will discuss the challenges of finding novel natural products with anti-TB activity from marine microbes and plant medicines, including biodiversity- and taxonomy-guided microbial natural products library construction, target- and cell-based HTS, and bioassay-directed isolation of anti-TB substances from traditional medicines.     

Current status, strategies, and potential for the metabolic engineering of heterologous polyketides in Escherichia coli

Heterologous natural product biosynthesis has emerged as a strategy to produce medicinal compounds that pose challenges to conventional production routes. Polyketide compounds, an important class of natural products with wide-ranging therapeutic value, have been heterologously produced through Escherichia coli, presenting new opportunities to realize the medicinal potential of polyketide natural products. However, current production levels are often suboptimal when compared to native strain producers or heterologous theoretical yields. This problem provides an excellent opportunity to apply and further develop current metabolic engineering tools.     

The benefits of the multi-target approach in drug design and discovery

Promiscuous binding has been considered to be a problem in the design and development of new drugs against a given disease. However, promiscuity in molecular recognition is not all bad news, and scientists are currently taking advantage of the emerging 'promiscuous binding' or 'multi-target approach' in medicinal chemistry.