Secondary Metabolism in Human Aerodigestive Microbiomes

This is a network showing different colored nodes and edges. Each node represent a biosynthetic gene cluster enriched in a different site of the aerodigestive tract.

In contrast to the gastrointestinal tract, the oral and respiratory tracts (collectively called the aerodigestive tract [ADT]) directly face the external environment. Therefore, in addition to competing among themselves, members of these ADT microbiomes compete with exogenous microbes from the external environment, including human pathogens, and act as a barrier against colonization of the lower digestive and respiratory tracts by invaders.

This diagram shows that the aerodigestive tract is the primary portal to the human body. The oral and respiratory microbiota interface with the external environment

As one means to compete, these bacteria may produce antibiotics and other bioactive secondary metabolites. We were interested in characterizing the biosynthetic potential of human ADT tract microbiomes to produce secondary metabolites.

In bacteria and other microbes, the genes responsible for production of antibiotics and other metabolites are organized in genomic loci called biosynthetic gene clusters (BGCs). These BGCs encode proteins necessary for biosynthesis, regulation, export, and self-resistance to antibiotics. By characterizing the protein domains contained within synthetases and identifying the other biosynthetic enzymes encoded by a given BGC, one may classify the type of secondary metabolite it encodes. For some chemical classes, in particular with nonribosomal peptide and type I polyketide BGCs, the core structure encoded may be inferred by understanding the logic of assembly line enzymology. Bioinformatic approaches have been developed that enable the identification of putative BGCs from genomic and metagenomic sequences, leading to the identification of secondary metabolites in a genome-first manner.

Secondary metabolism extends the central dogma of molecular biology. DNA is transcribed into RNA. RNA is translated into peptides. These peptides can be modified into secondary metabolites or function as secondary metabolite synthases. The genes for secondary metabolite biosynthesis, transport, and resistance are encoded in loci called biosynthetic gene clusters.

In previous work, we found that human aerodigestive tract microbiomes possess extensive potential for the biosynthesis of secondary metabolites and other bioactive natural products.

Graphs showing counts of different kinds of BGCs identified from aerodigestive tract bacteria and the types of bacteria that encode them. The most common types of biosynthetic gene clusters in the aerodigestive tract are RiPPs, NRPS, and terpenes. The most common bacterial producerrs are Streptococcus, Corynebacterium, and Staphylococcus.

The vast majority of the BGCs from these bacteria remain uncharacterized, but given examples of secondary metabolites mediating competitive interactions in the nasal cavity through siderophore and antibiotic activities, it is likely that these BGCs encode metabolites that affect interactions between members of the ADT microbiota. These interactions may contribute to population dynamics and spatial patterning of the microbiota across the ADT.

Future studies in our laboratory will combine complementary approaches, including genomics, metagenomics, transcriptomics, bacteria interaction assays, and analytical chemistry techniques to enable the discovery of new secondary metabolites from ADT bacteria, inform our understanding of ecology and biogeography of the ADT, and provide insight into the role these metabolites play in situ.