Listeria monocytogenes’ Step-Like Response to Sub-Lethal Concentrations of Nisin

Microbial safety of food products is often accomplished by the formulation of food-grade preservatives into the product. Because of the growing consumer demand for natural substances (including preservatives) in the composition of consumed foods, there is also a growing interest in the natural antimicrobial nisin, which has generally recognized as safe (GRAS) status for certain applications. During the products storage time, concentrations of preservative(s) are decreasing, which may eventually cause a serious problem in the food’s microbial safety. Here, for the first time we report on the non-linear response of a foodborne pathogen, Listeria monocytogenes, to sub-lethal concentrations of nisin.     

Natural Gas Operations from a Public Health Perspective

The technology to recover natural gas depends on undisclosed types and amounts of toxic chemicals. A list of 944 products containing 632 chemicals used during natural gas operations was compiled. Literature searches were conducted to determine potential health effects of the 353 chemicals identified by Chemical Abstract Service (CAS) numbers. More than 75% of the chemicals could affect the skin, eyes, and other sensory organs, and the respiratory and gastrointestinal systems. Approximately 40–50% could affect the brain/nervous system, immune and cardiovascular systems, and the kidneys; 37% could affect the endocrine system; and 25% could cause cancer and mutations. These results indicate that many chemicals used during the fracturing and drilling stages of gas operations may have long-term health effects that are not immediately expressed. In addition, an example was provided of waste evaporation pit residuals that contained numerous chemicals on the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) and Emergency Planning and Community Right-to-Know Act (EPCRA) lists of hazardous substances. The discussion highlights the difficulty of developing effective water quality monitoring programs. To protect public health we recommend full disclosure of the contents of all products, extensive air and water monitoring, coordinated environmental/human health studies, and regulation of fracturing under the U.S. Safe Drinking Water Act.     

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。     

Problems Related to the Use of Food Additives in the United States

Major problems encountered by enforcement agencies and by regulated industries, respectively, in implementing and conforming to recent food additive laws are reviewed. Decisions as to which substances fall within the broad terms of the legal definition, and which escape by virtue of “generally recognized as safe” (GRAS) status, are often difficult and complex. Distinctions cannot be made solely on the basis of whether substances are old or new, natural or synthetic. Registration of pesticides on a “no residue” basis and establishment of “zero tolerances” for food additives have created an anomalous situation as a result of improvements in sensitivity of analytical techniques which revealed the presence of minute amounts of substances where none were believed to exist. A solution has been recommended by a specially appointed committee of the National Academy of Sciences-National Research Council (U.S.A.). Enforcement of the new food additive laws warrants revision of present labelling requirements to provide for designating chemical ingredients by functional categories rather than by confusing chemical terminology.     

Development of GRAS strains for nutraceutical production using systems and synthetic biology approaches: advances and prospects

Nutraceuticals are food substances with medical and health benefits for humans. Limited by complicated procedures, high cost, low yield, insufficient raw materials, resource waste, and environment pollution, chemical synthesis and extraction are being replaced by microbial synthesis of nutraceuticals. Many microbial strains that are generally regarded as safe (GRAS) have been identified and developed for the synthesis of nutraceuticals, and significant nutraceutical production by these strains has been achieved. In this review, we systematically summarize recent advances in nutraceutical research in terms of physiological effects on health, potential applications, drawbacks of traditional production processes, characteristics of production strains, and progress in microbial fermentation. Recent advances in systems and synthetic biology techniques have enabled comprehensive understanding of GRAS strains and its wider applications. Thus, these microbial strains are promising cell factories for the commercial production of nutraceuticals.     

Importance of systems biology in engineering microbes for biofuel production

Microorganisms have been rich sources for natural products, some of which have found use as fuels, commodity chemicals, specialty chemicals, polymers, and drugs, to name a few. The recent interest in production of transportation fuels from renewable resources has catalyzed numerous research endeavors that focus on developing microbial systems for production of such natural products. Eliminating bottlenecks in microbial metabolic pathways and alleviating the stresses due to production of these chemicals are crucial in the generation of robust and efficient production hosts. The use of systems-level studies makes it possible to comprehensively understand the impact of pathway engineering within the context of the entire host metabolism, to diagnose stresses due to product synthesis, and provides the rationale to cost-effectively engineer optimal industrial microorganisms.     

Lactic acid bacteria as a tool for biovanillin production: A review

Vanilla is the most commonly used natural flavoring agent in industries like food, flavoring, medicine, and fragrance. Vanillin can be obtained naturally, chemically, or through a biotechnological process. However, the yield from vanilla pods is low and does not meet market demand, and the use of vanillin produced by chemical synthesis is restricted in the food and pharmaceutical industries. As a result, the biotechnological process is the most efficient and cost-effective method for producing vanillin with consumer-demanding properties while also supporting industrial applications. Toxin-free biovanillin production, based on renewable sources such as industrial wastes or by-products, is a promising approach. In addition, only natural-labeled vanillin is approved for use in the food industry. Accordingly, this review focuses on biovanillin production from lactic acid bacteria (LAB), which is generally recognized as safe (GRAS), and the cost-cutting efforts that are utilized to improve the efficiency of biotransformation of inexpensive and readily available sources. LABs can utilize agro-wastes rich in ferulic acid to produce ferulic acid, which is then employed in vanillin production via fermentation, and various efforts have been applied to enhance the vanillin titer. However, different designs, such as response surface methods, using immobilized cells or pure enzymes for the spontaneous release of vanillin, are strongly advised.     

Cytochrome P450 oxidations in the generation of reactive electrophiles: epoxidation and related reactions

Much of the interest in the cytochrome P450 (P450) enzymes has been because of oxidation of chemicals to reactive products. The epoxides (oxiranes) have been a major topic of interest with olefins and aryl compounds. Epoxides vary considerably in their reactivity, with t(1/2) varying from 1s to several hours. The stability and reactivity influences not only the overall damage to biological systems but also the site of injury. Transformations of some xenobiotic chemicals may involve products other than epoxides. Chemicals considered here include olefins, aromatic hydrocarbons, heterocycles, vinyl halides, ethyl carbamate, vinyl nitrosamines, and aflatoxin B(1). These compounds either are unsaturated or are transformed to unsaturated products. The epoxides and other products provide a view of the landscape of P450-generated reactive products and the myriad of chemistry involved in the metabolism of drugs and protoxicants. Understanding the chemical nature of reactive products is necessary to develop rational strategies for intervention.     

Bio-mining the microbial treasures of the ocean: new natural products

The biological resources of the oceans have been exploited since ancient human history, mainly by catching fish and harvesting algae. Research on natural products with special emphasis on marine animals and also algae during the last decades of the 20th century has revealed the importance of marine organisms as producers of substances useful for the treatment of human diseases. Though a large number of bioactive substances have been identified, some many years ago, only recently the first drugs from the oceans were approved. Quite astonishingly, the immense diversity of microbes in the marine environments and their almost untouched capacity to produce natural products and therefore the importance of microbes for marine biotechnology was realized on a broad basis by the scientific communities only recently. This has strengthened worldwide research activities dealing with the exploration of marine microorganisms for biotechnological applications, which comprise the production of bioactive compounds for pharmaceutical use, as well as the development of other valuable products, such as enzymes, nutraceuticals and cosmetics. While the focus in these fields was mainly on marine bacteria, also marine fungi now receive growing attention. Although culture-dependent studies continue to provide interesting new chemical structures with biological activities at a high rate and represent highly promising approaches for the search of new drugs, exploration and use of genomic and metagenomic resources are considered to further increase this potential. Many efforts are made for the sustainable exploration of marine microbial resources. Large culture collections specifically of marine bacteria and marine fungi are available. Compound libraries of marine natural products, even of highly purified substances, were established. The expectations into the commercial exploitation of marine microbial resources has given rise to numerous institutions worldwide, basic research facilities as well as companies. In Europe, recent activities have initiated a dynamic development in marine biotechnology, though concentrated efforts on marine natural product research are rare. One of these activities is represented by the Kieler Wirkstoff-Zentrum KiWiZ, which was founded in 2005 in Kiel (Germany).     

Potential Compounds for Oral Cancer Treatment: Resveratrol,Nimbolide, Lovastatin,Bortezomib, Vorinostat,Berberine, Pterostilbene,Deguelin, Andrographolide,and Colchicine

Oral cancer is one of the main causes of cancer-related deaths in South-Asian countries. There are very limited treatment options available for oral cancer. Research endeavors focused on discovery and development of novel therapies for oral cancer, is necessary to control the ever rising oral cancer related mortalities. We mined the large pool of compounds from the publicly available compound databases, to identify potential therapeutic compounds for oral cancer. Over 84 million compounds were screened for the possible anti-cancer activity by custom build SVM classifier. The molecular targets of the predicted anti-cancer compounds were mined from reliable sources like experimental bioassays studies associated with the compound, and from protein-compound interaction databases. Therapeutic compounds from DrugBank, and a list of natural anti-cancer compounds derived from literature mining of published studies, were used for building partial least squares regression model. The regression model thus built, was used for the estimation of oral cancer specific weights based on the molecular targets. These weights were used to compute scores for screening the predicted anti-cancer compounds for their potential to treat oral cancer. The list of potential compounds was annotated with corresponding physicochemical properties, cancer specific bioactivity evidences, and literature evidences. In all, 288 compounds with the potential to treat oral cancer were identified in the current study. The majority of the compounds in this list are natural products, which are well-tolerated and have minimal side-effects compared to the synthetic counterparts. Some of the potential therapeutic compounds identified in the current study are resveratrol, nimbolide, lovastatin, bortezomib, vorinostat, berberine, pterostilbene, deguelin, andrographolide, and colchicine.     

SWEETLEAD: an In Silico Database of Approved Drugs,Regulated Chemicals,and Herbal Isolates for Computer-Aided Drug Discovery

In the face of drastically rising drug discovery costs, strategies promising to reduce development timelines and expenditures are being pursued. Computer-aided virtual screening and repurposing approved drugs are two such strategies that have shown recent success. Herein, we report the creation of a highly-curated in silico database of chemical structures representing approved drugs, chemical isolates from traditional medicinal herbs, and regulated chemicals, termed the SWEETLEAD database. The motivation for SWEETLEAD stems from the observance of conflicting information in publicly available chemical databases and the lack of a highly curated database of chemical structures for the globally approved drugs. A consensus building scheme surveying information from several publicly accessible databases was employed to identify the correct structure for each chemical. Resulting structures are filtered for the active pharmaceutical ingredient, standardized, and differing formulations of the same drug were combined in the final database. The publically available release of SWEETLEAD (https://simtk.org/home/sweetlead) provides an important tool to enable the successful completion of computer-aided repurposing and drug discovery campaigns.     

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.     

The structural basis of the carcinogenic and mutagenic potentials of phytoalexins

CASE, a structure-activity relational system, was used to predict the proportion of substances to be carcinogenic and mutagenic among plant pesticides (phytoalexins) and other natural products compared to that of randomly selected chemicals. There were no significant differences between phytoalexins and other natural products. On the other hand, the natural products, as a group, were predicted to be less mutagenic and carcinogenic than randomly selected chemicals. 37% of natural products are predicted to be rodent carcinogens.     

Bioactive Peptides from Marine Ascidians and Future Drug Development–A Review

Marine ascidians are considered as one of the richest sources of bioactive compounds. The extraction and utilization of marine peptides have been attracted much attention owing to their potential health benefits. Most of the bioactive compounds from marine ascidians are already in different phases of the clinical and preclinical pipeline. They can be used in different functional and nutraceutical values due to their antineoplastic, antihypertensive, antioxidant, and antimicrobial properties. The screening in vivo and in vitro bioassays are coupled to the purification process for the exploration of its biological interest which is of great value. The growing significance to study marine natural products results from the discovery of novel pharmacological tools including potent anticancer drugs and other drugs are in clinical/pre-clinical trials. The present review highlights the recent research progress in marine ascidians’ peptides and its prospects for the future pharmaceutical development.     

Natural product drug discovery: the successful optimization of ISP-1 and halichondrin B

The concept that natural products provide excellent leads for drug discovery, ultimately producing viable drugs, is a widely accepted view. Natural products embody inherent structural complexity and biological activity which often leads to new targets, pathways, or modes of action. The challenge lies in identifying quality natural product scaffolds that can ultimately result in a drug. Two recently approved drugs originating from unlikely natural product leads, ISP-1 and halichondrin B, were examples of such high quality scaffolds. In initial testing, both compounds displayed excellent in vitro potency, but more importantly were amenable to chemical optimization. This combination of unique biological activity plus the generation of structural activity relationships (SAR) may be early indicators of a high quality natural product scaffold worthy of additional studies.     

Strategies for dereplication of natural compounds using high-resolution tandem mass spectrometry

Complete structural elucidation of natural products is commonly performed by nuclear magnetic resonance spectroscopy (NMR), but annotating compounds to most likely structures using high-resolution tandem mass spectrometry is a faster and feasible first step. The CASMI contest 2016 (Critical Assessment of Small Molecule Identification) provided spectra of eighteen compounds for the best manual structure identification in the natural products category. High resolution precursor and tandem mass spectra (MS/MS) were available to characterize the compounds. We used the Seven Golden Rules, Sirius2 and MS-FINDER software for determination of molecular formulas, and then we queried the formulas in different natural product databases including DNP, UNPD, ChemSpider and REAXYS to obtain molecular structures. We used different in-silico fragmentation tools including CFM-ID, CSI:FingerID and MS-FINDER to rank these compounds. Additional neutral losses and product ion peaks were manually investigated. This manual and time consuming approach allowed for the correct dereplication of thirteen of the eighteen natural products.     

Computational-aided design of a library of lactams through a diversity-oriented synthesis strategy

Small molecule libraries for virtual screening are becoming a well-established tool for the identification of new hit compounds. As for experimental assays, the library quality, defined in terms of structural complexity and diversity, is crucial to increase the chance of a successful outcome in the screening campaign. In this context, Diversity-Oriented Synthesis has proven to be very effective, as the compounds generated are structurally complex and differ not only for the appendages, but also for the molecular scaffold. In this work, we automated the design of a library of lactams by applying a Diversity-Oriented Synthesis strategy called Build/Couple/Pair. We evaluated the novelty and diversity of these compounds by comparing them with lactam moieties contained in approved drugs, natural products, and bioactive compounds from ChEMBL. Finally, depending on their scaffold we classified them into β-, γ-, δ-, ε-, and isolated, fused, bridged and spirolactam groups and we assessed their drug-like and lead-like properties, thus providing the value of this novel in silico designed library for medicinal chemistry applications.     

Patent and Exclusivity Status of Essential Medicines for Non-Communicable Disease

Objective

The threat of non-communicable diseases (“NCDs”) is increasingly becoming a global health crisis and are pervasive in high, middle, and low-income populations resulting in an estimated 36 million deaths per year. There is a need to assess intellectual property rights (“IPRs”) that may impede generic production and availability and affordability to essential NCD medicines.

Methods

Using the data sources listed below, the study design systematically eliminated NCD drugs that had no patent/exclusivity provisions on API, dosage, or administration route. The first step identified essential medicines that treat certain high disease burden NCDs. A second step examined the patent and exclusivity status of active ingredient, dosage and listed route of administration using exclusion criteria outlined in this study.

Materials

We examined the patent and exclusivity status of medicines listed in the World Health Organization’s (“WHO”) Model List of Essential Drugs (Medicines) (“MLEM”) and other WHO sources for drugs treating certain NCDs. i.e., cardiovascular and respiratory disease, cancers, and diabetes. We utilized the USA Food and Drug Administration Orange Book and the USA Patent and Trademark Office databases as references given the predominant number of medicines registered in the USA.

Results

Of the 359 MLEM medicines identified, 22% (79/359) address targeted NCDs. Of these 79, only eight required in-depth patent or exclusivity assessment. Upon further review, no NCD MLEM medicines had study patent or exclusivity protection for reviewed criteria.

Conclusions

We find that ensuring availability and affordability of potential generic formulations of NCD MLEM medicines appears to be more complex than the presence of IPRs with API, dosage, or administration patent or exclusivity protection. Hence, more sophisticated analysis of NCD barriers to generic availability and affordability should be conducted in order to ensure equitable access to global populations for these essential medicines.     

From tradition to innovation: the search for novel therapeutic molecules to treat diabetes

There are over a hundred chemical substances that have been derived from plants for use as drugs and medicines; many more await and medicinal plants are the target of all the attention. The structural diversity of natural products still surpasses that from synthetic compounds and is far beyond any imagination of experts in the field. For many pharmaceutical companies, it is a good argument to investigate natural compounds. Many plants with antidiabetic virtues are known in traditional medicine over the world. The CPID (Centre de Pharmacologie et Innovation dans le Diabète) proposes a technology program to purify new natural antidiabetic substances. A large antidiabetic plant library is constructed for a high-throughput pharmacological screening with cell cultures.