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The article argue that antibiotics are not monolithic in their response to economic incentives and that pathogen-selective antibiotics exhibit certain economic features that compel development of a different set of incentives. Topics discussed include history and nature of the antibiotic crisis; and contextual relationship between the drug, the doctor, the disease, and society.

The hygrolides, a family of 16-member-ring-containing plecomacrolides produced by Actinobacteria, exhibit numerous reported bioactivities. Using HR-MS/MS, nucleophilic 1,4-addition-based labeling, NMR, and bioinformatic analysis, we identified Streptomyces varsoviensis as a novel producer of JBIR-100, a fumarate-containing hygrolide, and elucidated the previously unknown stereochemistry of the natural product. We investigated the antimicrobial activity of JBIR-100, with preliminary insight into mode of action indicating that it perturbs the membrane of Bacillus subtilis . S. varsoviensis is known to produce compounds from multiple hygrolide sub-families, namely hygrobafilomycins (JBIR-100 and hygrobafilomycin) and bafilomycins (bafilomycin C 1 and D). In light of this, we identified the biosynthetic gene cluster for JBIR-100, which, to our knowledge, represents the first reported for a hygrobafilomycin. Finally, we performed a bioinformatic analysis of the hygrolide family, describing clusters from known and predicted producers. Our results indicate that potential remains for the Actinobacteria to yield novel hygrolide congeners, perhaps with differing biological activities. [ABSTRACT FROM AUTHOR]

Summary Natural products are the most historically significant source of compounds for drug development. However, unacceptably high rates of compound rediscovery associated with large-scale screening of common microbial producers have resulted in the abandonment of many natural product drug discovery efforts, despite the increasing prevalence of clinically problematic antibiotic resistance. Screening of underexplored taxa represents one strategy to avoid rediscovery. Herein we report the discovery, isolation, and structural elucidation of streptomonomicin (STM), an antibiotic lasso peptide from Streptomonospora alba, and report the genome for its producing organism. STM-resistant clones of Bacillus anthracis harbor mutations to walR , the gene encoding a response regulator for the only known widely distributed and essential two-component signal transduction system in Firmicutes. To the best of our knowledge, Streptomonospora had been hitherto biosynthetically and genetically uncharacterized, with STM being the first reported compound from the genus. Our results demonstrate that understudied microbes remain fruitful reservoirs for the rapid discovery of novel, bioactive natural products. [ABSTRACT FROM AUTHOR]

The biosynthesis of the thiopeptide thiomuracin is a well-orchestrated process involving a multitude of posttranslational modifications. We show that six Cys residues of a precursor peptide are first cyclodehydrated and oxidized to thiazoles in an ordered, but nonlinear fashion that is leader-peptide-dependent. Then four alcohols are glutamylated and converted to alkenes in a C-to-N terminal directional process that is leader-peptide-independent. Finally, two of these alkenes undergo a formal [4 + 2] cycloaddition to form a trithiazole-substituted pyridine macrocycle. We describe here the factors that govern the substrate specificity and order of biosynthetic events that turn a ribosomal peptide into a powerful antibiotic. [ABSTRACT FROM AUTHOR]