Chemical Perturbation of Secondary Metabolism Demonstrates Important Links to Primary Metabolism

SummaryBacterially produced secondary metabolites are used as antibiotics, anticancer drugs, and for many other medicinal applications. The mechanisms that limit the production of these molecules in the laboratory are not well understood, and this has impeded the discovery of many important compounds. We have identified small molecules that remodel the yields of secondary metabolites in many actinomycetes and show that one set of these molecules does so by inhibiting fatty acid biosynthesis. This demonstrates a particularly intimate relationship between this primary metabolic pathway and secondary metabolism and suggests an approach to enhance the yields of metabolites for discovery and biochemical characterization

Evidence for a Heterogeneous Distribution of Water in the Martian Interior

The abundance and distribution of H2O within the terrestrial planets, as well as its timing of delivery, is a topic of vital importance for understanding the chemical and physical evolution of planets and their potential for hosting habitable environments. Analysis of planetary materials from Mars, the Moon, and the eucrite parent body (i.e., asteroid 4Vesta) have confirmed the presence of H2O within their interiors. Moreover, H and N isotopic data from these planetary materials suggests H2O was delivered to the inner solar system very early from a common source, similar in composition to the carbonaceous chondrites. Despite the ubiquity of H2O in the inner Solar System, the only destination with any prospects for past or present habitable environments at this time, outside of the Earth, is Mars. Although the presence of H2O within the martian interior has been confirmed, very little is known regarding its abundance and distribution within the martian interior and how the martian water inventory has changed over time. By combining new analyses of martian apatites within a large number of martian meteorite types with previously published volatile data and recently determined mineral-melt partition coefficients for apatite, we report new insights into the abundance and distribution of volatiles in the martian crust and mantle. Using the subset of samples that did not exhibit crustal contamination, we determined that the enriched shergottite mantle source has 36-73 ppm H2O and the depleted shergottite mantle source has 14-23 ppm H2O. This result is consistent with other observed geochemical differences between enriched and depleted shergottites and supports the idea that there are at least two geochemically distinct reservoirs in the martian mantle. We also estimated the H2O content of the martian crust using the revised mantle H2O abundances and known crust-mantle distributions of incompatible lithophile elements. We determined that the bulk martian crust has approximately 1400 ppm H2O, which is likely distributed toward the martian surface. This crustal water abundance would equate to a global equivalent layer (GEL) of water at a depth of-229 m, which can account for at least some of the surface features on Mars attributed to flowing water and may be sufficient to support the past presence of a shallow sea on Mars' surface

An oxindole efflux inhibitor potentiates azoles and impairs virulence in the fungal pathogen Candida auris

Candida auris is an emerging fungal pathogen that exhibits resistance to multiple drugs, including the most commonly prescribed antifungal, fluconazole. Here, we use a combinatorial screening approach to identify a bis-benzodioxolylindolinone (azoffluxin) that synergizes with fluconazole against C. auris. Azoffluxin enhances fluconazole activity through the inhibition of efflux pump Cdr1, thus increasing intracellular fluconazole levels. This activity is conserved across most C. auris clades, with the exception of clade III. Azoffluxin also inhibits efflux in highly azole-resistant strains of Candida albicans, another human fungal pathogen, increasing their susceptibility to fluconazole. Furthermore, azoffluxin enhances fluconazole activity in mice infected with C. auris, reducing fungal burden. Our findings suggest that pharmacologically targeting Cdr1 in combination with azoles may be an effective strategy to control infection caused by azole-resistant isolates of C. auris.U01 TR002625 - NCATS NIH HHS; MOP-133636 - CIHR; U19 AI110818 - NIAID NIH HHS; R35 GM118173 - NIGMS NIH HHS; FDN-154288 - CIHR; R01 AI141202 - NIAID NIH HHS; R01 AI073289 - NIAID NIH HHSPublished versio

Principles of Microeconomics - Scarcity and Social Provisioning

Principles of Microeconomics: Scarcity and Social Provisioning takes a pluralistic approach to the standard topics of an introductory microeconomics course. The text builds on the chiefly neoclassical material of the OpenStax Principles of Economics text, adding extensive content from heterodox economic thought. Emphasizing the importance of pluralism and critical thinking, the text presents the method and theory of neoclassical economics alongside critiques thereof and heterodox alternatives in both method and theory. This approach is taken from the outset of the text, where contrasting definitions of economics are discussed in the context of the various ways in which neoclassical and heterodox economists study the subject. The same approach–of theory and method, critique, and alternative theory theory and method–is taken in the study of consumption, production, and market exchange, as well as in the applied theory chapters. Historical and contemporary examples are given throughout, and both theory and application are presented with a balanced approach.This textbook will be of interest especially to instructors and students who wish to go beyond the traditional approach to the fundamentals of microeconomic theory, and explore the wider spectrum of economic thought

Natural Products Repertoire of the Red Sea

Marine natural products have achieved great success as an important source of new lead compounds for drug discovery. The Red Sea provides enormous diversity on the biological scale in all domains of life including micro- and macro-organisms. In this review, which covers the literature to the end of 2019, we summarize the diversity of bioactive secondary metabolites derived from Red Sea micro- and macro-organisms, and discuss their biological potential whenever applicable. Moreover, the diversity of the Red Sea organisms is highlighted as well as their genomic potential. This review is a comprehensive study that compares the natural products recovered from the Red Sea in terms of ecological role and pharmacological activities

Activity-Independent Discovery of Secondary Metabolites Using Chemical Elicitation and Cheminformatic Inference

Most existing antibiotics were discovered through screens of environmental microbes, particularly the streptomycetes, for the capacity to prevent the growth of pathogenic bacteria. This “activity-guided screening” method has been largely abandoned because it repeatedly rediscovers those compounds that are highly expressed during laboratory culture. Most of these metabolites have already been biochemically characterized. However, the sequencing of streptomycete genomes has revealed a large number of “cryptic” secondary metabolic genes that are either poorly expressed in the laboratory or that have biological activities that cannot be discovered through standard activity-guided screens. Methods that reveal these uncharacterized compounds, particularly methods that are not biased in favor of the highly expressed metabolites, would provide direct access to a large number of potentially useful biologically active small molecules. To address this need, we have devised a discovery method in which a chemical elicitor called Cl-ARC is used to elevate the expression of cryptic biosynthetic genes. We show that the resulting change in product yield permits the direct discovery of secondary metabolites without requiring knowledge of their biological activity. We used this approach to identify three rare secondary metabolites and find that two of them target eukaryotic cells and not bacterial cells. In parallel, we report the first paired use of cheminformatic inference and chemical genetic epistasis in yeast to identify the target. In this way, we demonstrate that oxohygrolidin, one of the eukaryote-active compounds we identified through activity-independent screening, targets the V1 ATPase in yeast and human cells and secondarily HSP90