Natural products as mediators of disease

Abstract

Covering: up to 2016Humans are walking microbial ecosystems, each harboring a complex microbiome with the genetic potential to produce a vast array of natural products. Recent sequencing data suggest that our microbial inhabitants are critical for maintaining overall health. Shifts in microbial communities have been correlated to a number of diseases including infections, inflammation, cancer, and neurological disorders. Some of these clinically and diagnostically relevant phenotypes are a result of the presence of small molecules, yet we know remarkably little about their contributions to the health of individuals. Here, we review microbe-derived natural products as mediators of human disease.

Figure 1. Factors Affecting Microbial Dysbiosis

Microbiome composition can be affected by a number of factors including, but not limited to, genetic predisposition, clinical treatment, microbiome acquired at birth, diet, and other lifestyle factors.

Figure 2. Microbial-derived Natural Products in Human Disease

Microbes involved in mediating human disease produce a structurally diverse array of natural products. While we illustrate characterized molecules, many metabolites involved in microbe-driven disease remain structurally unresolved including streptolysin S and listerioslysin S, metabolites recognized for their hemolytic activities.

Figure 3. In vitro Chemical Interactions of P. aeruginosa and A. fumigatus

P. aeruginosa produces several redox active phenazines including pyocyanin (PYO), phenazine-1-carboxylic acid (PCA), and 1-hydroxyphenazine (1-HP). A. fumigatus modifies the phenazines by producing dimers and biotransforming PCA to 1-HP. 1-HP is further modified to 1-methoxyphenazine and phenazine-1-sulfate. A. fumigatus uses 1-HP to induce its own triacetylfusarinine C and fusarinine C siderophore production. P. aeruginosa phenazines also lead to the production of reactive oxygen and nitrogen species in A. fumigatus.

Figure 4. Precolibactin Structures

Immense effort to elucidate both the structure and biosynthetic pathway of colibactin has been taken. At least 10 precolibactins have been structurally characterized. The metabolites shown were chosen to represent the structural variations described.