Abstract
The biotech industry has dramatically contributed to the extension of human life span. One of the most important successes are antibiotics, which have saved millions of lives worldwide since their introduction in the 1940s. However, their increased use has also lead to a gradual increase in antibiotic resistance in bacterial populations. This has resulted in a turning-point where we now face a huge challenge in treating infections by multiresistant bacteria. Most clinically relevant antibiotics are derived from filamentous bacteria called actinomycetes, which also produce many other relevant natural products including antifungal and anticancer agents. The genetic information to produce these molecules are often assembled in large gene clusters, which are abundantly found in the genomes of actinomycetes. Recent sequencing technologies have given us access to thousands of new biosynthetic gene clusters, which should drive the discovery of new drugs. One of the most promising tools is offered by synthetic biology, where these gene clusters are refactored and introduced in production hosts at large scale. To prevent self-killing, such hosts will also be equipped with appropriate resistance genes. While release of these producer strains in sewage and in the environment is unlikely, the synthetic DNA of these organism may end up in wastewater treatment plants before being released into nature. As such, these installations may represent a large, and underappreciated reservoir for the spread of antibiotic-resistance genes. This proposal aims to assess the risk of spread of antimicrobial resistance genes in the environment derived from currently used synthetic biology approaches in the field of drug discovery. Together with the industry, we will challenge how DNA spreads in the environment and is taken up by foreign microbes. Altogether, the combination of innovative methods of synthetic biology, whole-genome sequencing, and environmental biotechnology will result in the achievement of key milestones for the understanding of (i) 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. This project will foster engineering safety measures to remediate the spread of modified DNA and resistances in Nature and Health.
Netherlands