The 1st International BioDesign Research Conference December 1st - 18th, 2020, Virtual
Bridging the gap between drug discovery and synthetic biology: an alkaloid case study
Thomas Willems1†, Maarten L. De Mol1†*, Jeltien Rombaut1, Aleksandar De Bruycker1, Sofie L. De Maeseneire1, Wim K. Soetaert1
1InBio.be, Department of Biotechnology, Faculty of Bioscience Engineering, Ghent University, Gent, 9000, Belgium
*Corresponding author. Email: Maarten.DeMol@UGent.be
†These authors contributed equally to this work.
Background
Harnessing nature’s diversity for human benefit has proven a very successful strategy in pharmaceutical drug discovery. From salicin derived from willow bark and modified to the anti-inflammatory drug aspirin to the antibiotic streptomycin discovered in Streptomyces griseus, many organisms have developed specialty molecules to provide a competitive advantage over others. This has led researchers to closely investigate different environmental niches and develop plenty of screening methods to identify novel bioactive compounds exploitable for pharmaceutical use [1]. Due to the imminent threat of antimicrobial resistance and the dire consequences for our healthcare system, novel and innovative antibiotics are in high demand. Besides discovering new target compounds, an efficient production process is vital as well. Here, synthetic biology and industrial biotechnology provide an interesting edge over the natural producers as model organisms are better characterized and thus allow for more controllable engineering and production processes.
Methods
We have recently reviewed all newly discovered alkaloids with antimicrobial activity produced by marine fungi since 2015 [2].
Results
Although the microbial production of antimicrobial compounds seems counter-intuitive, the choice of suitable production host allows for the microbial synthesis of antimicrobials nonetheless. Such choice will be directed by the antimicrobial mode of action as certain molecules will solely be active against a subset of microbial production hosts. For example the aminoglycoside streptomycin selectively inhibits prokaryote protein synthesis while having no effect on eukaryotes, providing an edge for yeast production hosts. In addition to the antimicrobial properties of these alkaloids, many have been subjected to other application assays as well. The reviewed alkaloids in particular also possess cytotoxic, antioxidant, antiviral, anti-fouling and anti- acetylcholinesterase properties and have been investigated as plant growth stimulators.
Depending on their mode of action, these additional functionalities might be correlated to the antimicrobial activity. For example, the depletion of iron results in arresting the mammalian cell cycle in the G1 phase, disturbing cell division and resulting in inhibition of e.g. tumor growth. The choice of production host furthermore rests on the biochemical production pathway and the native metabolism of the hosts. Certain
The 1st International BioDesign Research Conference December 1st - 18th, 2020, Virtual
microorganisms intrinsically possess higher precursor pools of the desired molecule while others might be more suitable due to their regulatory background. Taken together, this poster visualizes two important aspects determining the choice of microbial production hosts for newly discovered compounds.
Conclusion
To date, many biochemical reaction steps in the synthesis of these alkaloids remain elusive. These hiatuses limit the current applicability of synthetic biology as a viable alternative for their production and thus require closer investigation. In addition, more thorough structure-activity studies are warranted as there might be a correlation between bioactivities such as tumor growth inhibition and antimicrobial activity.
Funding
This research was funded by the FWO in the framework of the PhD grant of Thomas Willems (Nr. 198258).
References
[1] De Mol M. L., Snoeck N., De Maeseneire S. L., Soetaert W. K. Biotechnology Advances 2018, 36(8), 2201-2218
[2] Willems T, De Mol M. L., De Bruycker A., De Maeseneire S. L., Soetaert W. K.
Antibiotics 2020, 9(6), 340
