The Bright Side of Microbial Dark Matter: An Untapped Source of Novel Natural Products Temporal changes in biosynthetic gene clusters of Phaeobacter spp.

The Bright Side of Microbial Dark Matter: An Untapped Source of Novel Natural Products

A fundamental question at the intersection between microbial ecology and biotechnology is how rich a repository of bioactive natural products (NPs) the microbial world is. An equally fundamental and highly timely question is ‘how can we exploit this richness?’

The advent of antibiotics in medicine is one of the most essential advances for human health. Regrettably, their use, and misuse, have led to the emergence of antibiotic resistance in bacteria, and this is currently outpacing the discovery of novel compounds making the rise of antibiotic resistance one of the greatest threats to human health. In this project, we try to procure novel antibacterial compounds by mining an underexplored source of bioactives, the as-yet uncultivable majority of microorganisms, or the so-called microbial dark matter.

More than 75 % of currently known antibiotics are derived from bioactive compounds produced by living organisms, and most of these are from microorganisms. However, since the end of the “golden era of antibiotic discovery” (1940s-1960s), very few new NPs have been introduced as systemic drugs. Despite the development of de-replication strategies, bioprospecting approaches are challenged by rediscovery of known compounds, meaning that novel leads are rarely found. A major obstacle is that we are currently only able to culture less than 1 % of all bacteria. As a consequence we know very little about the diversity of NPs produced by bacteria in situ. Considering that antibiotic activity is an inherent function of many bacterial secondary metabolites, and that NP-encoding gene clusters are present in microbial environmental DNA (eDNA), we hypothesize that the hidden NP diversity can be exploited by developing new cultivation strategies as well as through the implementation of novel cultivation-independent approaches. More information.

Temporal changes in biosynthetic gene clusters of Phaeobacter spp.

Bacteria from the marine alphaproteobacterial genus Phaeobacter carries the genetic capacity to produce bioactive secondary metabolites such as tropodithietic acid (TDA), which has broad-spectrum antimicrobial properties at high concentrations. However, at lower in situ concentrations, the effect of TDA on community members is subtle and highly specific, and hence the natural function of such compounds is likely not solely of an antimicrobial nature. The ambition of this project is to investigate whether temporal changes in the natural Phaeobacter community correlates with changes in the biosynthetic gene clusters (BGCs) and the corresponding phenotypes. This will give indications of whether or not the function of secondary metabolites such as TDA is conserved in Nature across a temporal scale.

This project is part of the Center of Excellence, Center for Microbial Secondary Metabolites, CeMiSt. The purpose of the Center, that involves several other faculty and students at DTU Bioengineering, is to unravel the role of microbial secondary metabolites in natural microbial systems.