Universiteit Leiden

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Research project

Horizontal gene transfer and spreading of biosynthetic gene clusters and antimicrobial resistance

Biosynthetic gene clusters (BGCs) for natural products are widespread in microbial genomes, and they are rapidly exchanged. This research assesses the factors that control the spread of BGCs and resistance genes in nature. This includes risk assessment for the spread of engineered DNA in nature.

2017 - 2022
Gilles van Wezel

Prof. Mark van Loosdrecht and Dr. David Weissbroth, Environmental Biotechnology group, TU Delft
Prof. Paul Jensen, Scripps Institute of Oceanography, San Diego, California
Dr. John Glass, J. Craig Venter Institute, San Diego, California
Dutch water boards (Wetsus)
National Institute for Public Health and the Environment (RIVM)

Novel antibiotics have been discovered in previously unexplored habitats or in yet to be cultured microbes. The genes responsible for the biosynthesis of secondary metabolites are typically clustered on the chromosome. Biosynthetic gene clusters evolve surprisingly rapidly as compared to other genetic elements, thus contributing to the high structural diversity of natural products. While the selective pressures driving secondary metabolite diversification are not known, the availability of large numbers of genome sequences has made it possible to begin to identify the evolutionary mechanisms that govern the biogenesis of structural novelty. Bacterial evolution and evolution of BGCs are independent of one another, and horizontal gene transfer (HGT) is a major driving force towards the chemical diversity of natural products. Indeed, actinomycetes and other bacteria readily exchange BGCs, which are among the most rapidly evolving genetic elements. One of the most promising tools to harness the enormous genome sequence information is offered by synthetic biology, where BGCs are refactored and introduced in production hosts at large scale.

Aim of this research is two fold. Firstly, we seek to understand the factors that control HGT as major driver of the diversity of the chemical space of natural products.

Secondly, we want to assess the risk of spreading of gene clusters and their resistance genes from genetically engineered strains into the environment. While release of producer strains in sewage and in the environment is unlikely, the synthetic DNA of these organisms may end up in wastewater treatment plants before being released into nature. We thereby seek to understand (i) the factors that control DNA exchange and resistance transmission between microorganisms, (ii) environmental and engineered factors that trigger exchange mechanisms, and (iii) the role that actinomycetes play in this process within natural and engineered microbiomes.

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