The molecular mechanisms of pentapeptide repeat proteins action on DNA gyrase elucidated by structural biology methods
About The Project
Bacterial resistance to antibiotics is one of the major problems of modern healthcare. Bacteria adapt themselves to the action of therapeutics in many ways: they shut down their metabolism, accumulate mutations in proteins affected by the drug, or acquire special resistance genes from their neighbours. Such transmissible resistance is dangerous because it can spread across the globe very rapidly. For example, resistance to a last-resort antibiotic, colistin, has spread from China to US only in a few months!
In the Heddle lab, we are studying mechanisms of transmissible resistance to fluoroquinolones - synthetic antibiotics, which used to be very successful but are now losing their efficiency. Fluoroquinolones inhibit DNA gyrase – an essential bacterial enzyme, which controls the topological state (twisting) of DNA. Resistance proteins (Qnr proteins) are thought to interact with the gyrase to prevent drugs from binding. We want to learn how Qnr-gyrase complex is organized to design better drugs not affected by the resistance.
Most interestingly, Qnr proteins can also help us in the search for new natural antibiotics. Qnr proteins appeared in nature long before humans: many bacteria produce gyrase toxins to compete with their rivals and they have to protect themselves from their own weapons. Screening bacterial genomes for gyrase-protecting proteins allows us to find novel natural products targeting gyrase.
What we are doing
Biochemistry: How different Qnr-related proteins affect gyrase activity?
Genetics: Which elements of gyrase-protecting proteins are important for their action?
Structural biology: What is the structure of the Qnr-gyrase complex?
Our Polonez Team
Dr. Dmitry Ghilarov, PhD: After several years of postdoctoral research on novel antibiotics in Russia and UK, NCN POLONEZ Fellowship funding allowed me to join the Heddle lab and lead a small team to investigate antibiotic resistance mediated by Qnr proteins
Lukasz Mazurek: Łukasz is a PhD student on the project which elements of gyrase-protecting proteins are important for their action?
Lizzi Michalczyk: Lizzi is an assistant working on the project. Joining after working in industry, Lizzi is a specialist in protein purification and gyrase activity tests how’s the Qnr-gyrase structure look like?
Iga Niemiec: Iga is out intern and is helping us make and test gyrase proteins.
Prof Roderich Suessmuth TU University in Berlin
Prof. Anthony Maxwell John Innes Centre UK
Dr. David Lawson John Innes Centre, UK
We are very grateful that this project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 665778.
Fellowship registration number: 2015/19/P/NZ1/03137