Class IIb Microcin MccM Interferes with Oxidative Phosphorylation in .

Dysbiosis of the human gut microbiota is linked to numerous diseases. Understanding the molecular mechanisms by which microbes interact and compete with one another is required for developing successful strategies to modulate the microbiome. The natural product Microcin M (MccM) consists of a 77-residue bioactive peptide conjugated to a siderophore and is a class II microcin involved in microbial competition with an enigmatic mode-of-action.

Investigation of Siderophore-Platinum(IV) Conjugates Reveals Differing Antibacterial Activity and DNA Damage Depending on the Platinum Cargo.

The growing threat of bacterial infections coupled with the dwindling arsenal of effective antibiotics has heightened the urgency for innovative strategies to combat bacterial pathogens, particularly Gram-negative strains, which pose a significant challenge due to their outer membrane permeability barrier. In this study, we repurpose clinically approved anticancer agents as targeted antibacterials. We report two new siderophore-platinum(IV) conjugates, both of which consist of an oxaliplatin-based Pt(IV) prodrug (oxPt(IV)) conjugated to enterobactin (Ent), a triscatecholate siderophore employed by Enterobacteriaceae for iron acquisition.

Metal sequestration by S100 proteins in chemically diverse environments.

During infection, the mammalian host initiates a metal-withholding response against invading microbial pathogens to inhibit their growth and survival, a process often termed 'nutritional immunity'. The host-defense S100 proteins calprotectin (CP) (S100A8/S100A9 oligomer), S100A12, and S100A7 play key roles in the innate immune response by sequestrating essential transition metal nutrients from microbes in the extracellular space. Accumulating evidence suggests that the antimicrobial activity of these proteins varies between infection sites and may be affected by the local chemical environment.

Glutamic acid is a carrier for hydrazine during the biosyntheses of fosfazinomycin and kinamycin.

Fosfazinomycin and kinamycin are natural products that contain nitrogen-nitrogen (N-N) bonds but that are otherwise structurally unrelated. Despite their considerable structural differences, their biosynthetic gene clusters share a set of genes predicted to facilitate N-N bond formation. In this study, we show that for both compounds, one of the nitrogen atoms in the N-N bond originates from nitrous acid.

New Insights into the Biosynthesis of Fosfazinomycin.

The biosynthetic origin of a unique hydrazide moiety in the phosphonate natural product fosfazinomycin is unknown. This study presents the activities of five proteins encoded in its gene cluster. The flavin dependent oxygenase FzmM catalyses the oxidation of L-Asp to -hydroxy-Asp.

Discovery of phosphonic acid natural products by mining the genomes of 10,000 actinomycetes.

Although natural products have been a particularly rich source of human medicines, activity-based screening results in a very high rate of rediscovery of known molecules. Based on the large number of natural product biosynthetic genes in microbial genomes, many have proposed "genome mining" as an alternative approach for discovery efforts; however, this idea has yet to be performed experimentally on a large scale. Here, we demonstrate the feasibility of large-scale, high-throughput genome mining by screening a collection of over 10,000 actinomycetes for the genetic potential to make phosphonic acids, a class of natural products with diverse and useful bioactivities.

Comparison of three magnetic bead surface functionalities for RNA extraction and detection.

Magnetic beads are convenient for extracting nucleic acid biomarkers from biological samples prior to molecular detection. These beads are available with a variety of surface functionalities designed to capture particular subsets of RNA. We hypothesized that bead surface functionality affects binding kinetics, processing simplicity, and compatibility with molecular detection strategies.

Biosynthesis of fosfazinomycin is a convergent process.

Fosfazinomycin A is a phosphonate natural product in which the C-terminal carboxylate of a Val-Arg dipeptide is connected to methyl 2-hydroxy-2-phosphono-acetate (Me-HPnA) via a unique hydrazide linkage. We report here that Me-HPnA is generated from phosphonoacetaldehyde (PnAA) in three biosynthetic steps through the combined action of an -methyltransferase (FzmB) and an α-ketoglutarate (α-KG) dependent non-heme iron dioxygenase (FzmG). Unexpectedly, the latter enzyme is involved in two different steps, oxidation of the PnAA to phosphonoacetic acid as well as hydroxylation of methyl 2-phosphonoacetate.