Date: 5th October 2019
Combining a computational algorithm with synthetic biology has allowed scientists to access biologically active small molecules encoded directly in human microbiome-derived metagenomic sequencing data.
Antibiotic resistance is one of the biggest threats to global health. In the US alone it is estimated 2 million people are infected with antibiotic-resistant bacteria, resulting in around 23,000 deaths a year.
In 1928 the Scottish scientist, Sir Alexander Fleming, now famed for his discovery, accidentally found the world’s first antibiotic, penicillin. Several years later, before penicillin was even introduced as a therapeutic drug, the first penicillin-resistant bacteria was described.
Antibiotics inhibit the growth or replication of a bacterium, and are produced in nature by soil bacteria and fungi. Antibiotic resistance occurs naturally over time, usually through genetic changes. However, increasing or over-use of antibiotics has accelerated the emergence of resistant strains, enabled by the extraordinary, flexible genetic capacities that microbes possess.
Now scientists from Princeton University have employed a novel computational approach to search the genome of human microbiota for genes that encode drug-like molecules.
The team used an algorithm called MetaBGC to scan the genome for short DNA sequences derived from microbe samples from the skin, gut and mouth. The team initially focused on Type II polyketide synthase (TII-PKS); an important natural metabolite that comprises the basic chemical structure of various anticancer, antifungal and antibacterial modulators.
The software scanned for overlapping DNA sequences encoding TII-PKS within the microbial metagenome to return the most promising candidates.
Subjected to several large datasets, and additional rounds of algorithm refinements, the team found 13 different clusters of new genes related to TII-PKS.
To test the properties of the newly discovered genes, the team introduced them back into common lab bacteria using synthetic biology methods and whilst none showed anti-cancer activities, two did show robust anti-bacterial characteristics.
Digital biology meets synthetic biology
We are always excited here at BioTechScope when our two favourite subjects combine to accelerate our knowledge and advance us towards new treatments and discoveries.
This method of scanning the metagenome paves the way for unfurling the chemical catalogue of the human microbiota. It also has the potential to shed light on molecular mediators of microbiome and host, and the interaction dynamics between microbiomes.
With the microbiome playing crucial roles in health and the immune system for example, and also being linked to a variety of conditions from obesity to anxiety, this is becoming an increasingly important field.
In this study, by basing the search on pathways fundamental to anticancer and antibacterial molecules, there is a huge potential for a new plethora of drugs to be discovered. One with the potential also to offer us hope in the battle against antibiotic resistance.
The association between microbiome and personalised medicine, whilst a relatively new field, is gathering momentum. This platform offers the synthetic biologist a powerful digital tool in the search for new molecules/treatments, and may offer us a handle on new possibilities for precision medicine.
Sugimoto, Y., F. R. Camacho, S. Wang, P. Chankhamjon, A. Odabas, A. Biswas, P. D. Jeffrey and M. S. Donia (2019). “A metagenomic strategy for harnessing the chemical repertoire of the human microbiome.” Science: eaax9176.
https://doi.org/10.1126/science.aax9176
