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Unlocking the antibiotic production potential in soil bacteria Streptomyces coelicolor

Periodic Reporting for period 1 - STREPUNLOCKED (Unlocking the antibiotic production potential in soil bacteria Streptomyces coelicolor)

Reporting period: 2019-10-18 to 2021-10-17

We're facing a post-antibiotic era in public healthcare. The need for novel antibiotics and other antimicrobial solutions is a worldwide issue. Finding new avenues for tackling this problem and feeding the discovery pipeline was the main intent of this project.
The main conclusion is that the bacteria themselves are a rich source of novel solutions, and what we found was not exactly what we aimed at in the beginning, but it fulfils the intent of it. Instead of a new antibiotic (up to this point), we found a bacterial toxin-neutralizing enzyme and started to unravel a way of finding novel agents that can inhibit microbial growth.
We used a bacterial system that naturally produces antibiotics and was already a major source of antibiotics and other anti-microbial drugs/targets in the past. We were studying a metabolism-altering set of genes/enzymes that caused the bacteria to boost their metabolism in favour of producing more antibiotics that we already know and hoped to find ways to tweak the system to find new ones. In the process, we realized that we stumbled upon a new enzyme that can neutralize the Mycobacterium tuberculosis toxin which is still a non-eradicated and potentially deadly world pathogen. Since we were in the midst of the world pandemic caused by a virus carrying a homologue (that is – a very similar enzyme to the M. tuberculosis toxin-neutralizing one), we expanded our study to include looking for the potential SARS-CoV2-MD (MD stands for a “macrodomain” type of protein/enzyme) inhibitors as well. We discovered the mode of action for the bacterial enzyme and learned new ways of finding a well-fitting inhibitor for the SARS-CoV2-MD protein. Results were presented at a renowned conference in the field, the initial project was covered by public media and a part of the project was published in a scientific peer-reviewed paper. Although no website has been developed for the project, it was a part of the running project: https://www.irb.hr/eng/Divisions/Division-of-Molecular-Biology/Laboratory-for-Molecular-Genetics/Projects/Understanding-the-role-of-protein-ADP-ribosylation-modification-in-bacteria
According to the WHO – the antibiotic resistance is one of the biggest threats to global health, food security, and development today. Bacterial species we are continuously studying – the Streptomyces, are the biggest producers of natural antibiotics. So far we are familiar with only a fraction of those. In addition, the Streptomyces have an astounding amount of genes, even half of the number in eukaryotes, most of which are still poorly characterized. Some of those have human counterparts involved in human disease development. The genes we ended up studying in more depth are a pair of one from Streptomyces bacterial species and its viral SARS-Cov2 homologue. They are in their function different, but similar in their structure, and very likely, in the way (the mechanism) of how they function and can be inhibited. So, the knowledge on the structure and the mechanism of action/inhibition we found, when integrated, give us insight into how new inhibitors for bacterial toxins and essential viral proteins can be designed. The same pipeline can be used in the future on any similar protein contained in any new pathogen – both in the bacteria and viruses.
Scheme of the STREPUNLOCKED main conclusions