Multi-arming ourselves against drug-resistant bacteria.

New classes of antibiotics are desperately needed in our fight against antibiotic-resistant bacterial infections. Jia et al. publish a new "multi-armed" antibiotic scaffold that effectively treats methicillin-resistant Staphylococcus aureus infections in mice.

Targeted Degradation of the Oncogenic Phosphatase SHP2.

SHP2 is a protein tyrosine phosphatase that plays a critical role in the full activation of the Ras-MAPK pathway upon stimulation of receptor tyrosine kinases, which are frequently amplified or mutationally activated in human cancer. In addition, activating mutations in SHP2 result in developmental disorders and hematologic malignancies. Several allosteric inhibitors have been developed for SHP2 and are currently in clinical trials.

Capsular polysaccharide correlates with immune response to the human gut microbe .

Active inflammatory bowel disease (IBD) often coincides with increases of , a gut microbe found in nearly everyone. It was not known how, or if, this correlation contributed to disease. We investigated clinical isolates of to identify molecular mechanisms that would link to inflammation.

Dolosigranulum pigrum Cooperation and Competition in Human Nasal Microbiota.

Multiple epidemiological studies identify as a candidate beneficial bacterium based on its positive association with health, including negative associations with nasal/nasopharyngeal colonization by the pathogenic species and Using a multipronged approach to gain new insights into function, we observed phenotypic interactions and predictions of genomic capacity that support the idea of a role for microbe-microbe interactions involving in shaping the composition of human nasal microbiota. We identified community-level and phenotypic cooperation by specific nasal species. Also, inhibited growth , whereas robust inhibition of required both and a nasal together.

Bariatric surgery reveals a gut-restricted TGR5 agonist with anti-diabetic effects.

Bariatric surgery, the most effective treatment for obesity and type 2 diabetes, is associated with increased levels of the incretin hormone glucagon-like peptide-1 (GLP-1) and changes in levels of circulating bile acids. The levels of individual bile acids in the gastrointestinal (GI) tract after surgery have, however, remained largely unstudied. Using ultra-high performance liquid chromatography-mass spectrometry-based quantification, we observed an increase in an endogenous bile acid, cholic acid-7-sulfate (CA7S), in the GI tract of both mice and humans after sleeve gastrectomy.

Research Tales from the Clardy Laboratory: Function-Driven Natural Product Discovery.

Over the past 70 years, the search for small molecules from nature has transformed biomedical research: natural products are the basis for half of all pharmaceuticals; the quest for total synthesis of natural products fueled development of methodologies for organic synthesis; and their biosynthesis presented unprecedented biochemical transformations, expanding our chemo-enzymatic toolkit. Initially, the discovery of small molecules was driven by bioactivity-guided fractionation. However, this approach yielded the frequent rediscovery of already known metabolites.

Pyonitrins A-D: Chimeric Natural Products Produced by .

Bacterial symbionts frequently provide chemical defenses for their hosts, and such systems can provide discovery pathways to new antifungals and structurally intriguing metabolites. This report describes a small family of naturally occurring small molecules with chimeric structures and a mixed biosynthesis that features an unexpected but key nonenzymatic step. An insect-associated strain's activity in an murine candidiasis assay led to the discovery of a family of highly hydrogen-deficient metabolites.

, a member of the human gut microbiome associated with Crohn's disease, produces an inflammatory polysaccharide.

A substantial and increasing number of human diseases are associated with changes in the gut microbiota, and discovering the molecules and mechanisms underlying these associations represents a major research goal. Multiple studies associate , a prevalent gut microbe, with Crohn's disease, a major type of inflammatory bowel disease. We have found that synthesizes and secretes a complex glucorhamnan polysaccharide with a rhamnose backbone and glucose sidechains.

Colibactin assembly line enzymes use S-adenosylmethionine to build a cyclopropane ring.

Despite containing an α-amino acid, the versatile cofactor S-adenosylmethionine (SAM) is not a known building block for nonribosomal peptide synthetase (NRPS) assembly lines. Here we report an unusual NRPS module from colibactin biosynthesis that uses SAM for amide bond formation and subsequent cyclopropanation. Our findings showcase a new use for SAM and reveal a novel biosynthetic route to a functional group that likely mediates colibactin's genotoxicity.

Modern mass spectrometry for synthetic biology and structure-based discovery of natural products.

Covering: up to 2016In this highlight, we describe the current landscape for dereplication and discovery of natural products based on the measurement of the intact mass by LC-MS. Often it is assumed that because better mass accuracy (provided by higher resolution mass spectrometers) is necessary for absolute chemical formula determination (≤1 part-per-million), that it is also necessary for dereplication of natural products. However, the average ability to dereplicate tapers off at ∼10 ppm, with modest improvement gained from better mass accuracy when querying focused databases of natural products.

New Aspercryptins, Lipopeptide Natural Products, Revealed by HDAC Inhibition in Aspergillus nidulans.

Unlocking the biochemical stores of fungi is key for developing future pharmaceuticals. Through reduced expression of a critical histone deacetylase in Aspergillus nidulans, increases of up to 100-fold were observed in the levels of 15 new aspercryptins, recently described lipopeptides with two noncanonical amino acids derived from octanoic and dodecanoic acids. In addition to two NMR-verified structures, MS/MS networking helped uncover an additional 13 aspercryptins.

Large-scale metabolomics reveals a complex response of Aspergillus nidulans to epigenetic perturbation.

The microbial world offers a rich source of bioactive compounds for those able to sift through it. Technologies capable of quantitatively detecting natural products while simultaneously identifying known compounds would expedite the search for new pharmaceutical leads. Prior efforts have targeted histone deacetylases in fungi to globally activate the production of new secondary metabolites, yet no study has directly assessed its effects with minimal bias at the metabolomic level.