New thesis shows alternative route towards future antibiotics
After screening more than 7 billion chemical compounds, researchers at Uppsala University have identified molecules with antibacterial activity against Gram-negative bacteria. “Our results show that DNA-encoded library technology can be a potentially effective way forward in the development of new antibiotics,” says Christodoulos Mitrogiannis, PhD student at the Department of Medicinal Chemistry.
The careless use of antibiotics has made antimicrobial resistance an urgent global concern. A key challenge is the difficulty of developing new drugs – and in a new thesis at Uppsala University, PhD student Christodoulos Mitrogiannis presents an alternative strategy for identifying compounds that can contribute to combating Gram-negative bacteria, ranked by the WHO among the greatest threats to public health.
Christodoulos Mitrogiannis & Colleagues at Uppsala Biomedical Centre
“Gram-negative bacteria surround themselves with protective membranes, making it more difficult for antibiotics to enter. New approaches are therefore needed, and we have chosen to focus on LpxH, an enzyme that bacteria need to build this membrane. Our idea is that the right molecule could block the enzyme, and to efficiently identify promising candidates, we have used DNA-encoded library technology,” says Christodoulos Mitrogiannis, PhD student at the Department of Medicinal Chemistry.
By designing a library of 403,200 DNA-encoded chemical compounds and successfully identifying which of them bound to a specific protein, Mitrogiannis validated the screening approach. In a second study, he developed a library of 1.3 million more three-dimensional and structurally rigid molecules and, through screening against LpxH, identified a chemotype with a probable ability to bind to the enzyme.
Research underway at the Department of Medicinal Chemistry Lab
“In our third study, we used a commercial library containing 7.2 billion compounds and observed antibacterial activity against, among others, E. coli and K. pneumoniae, which we were able to trace in the laboratory to inhibition of LpxH. Our results show that DNA-encoded chemical libraries can be a potentially effective way forward in the search for new antibiotics – and even before publication, our conclusions are attracting considerable scientific interest,” says Christodoulos Mitrogiannis.
The work was carried out within Uppsala University's research environment for Drug Design and Discovery. The same laboratory is also home to ENABLE-2, a European antibiotic platform which – following a SEK 100 million government investment – supports nine programmes in the early stages of development of promising antibiotic candidates.
“My time at the Department of Medicinal Chemistry has been a very positive experience. Working in an environment characterised by both generosity and freedom has enabled me to develop as an independent researcher, and following my dissertation I feel inspired to continue exploring antibiotics as well as DNA-encoded library technology,” says Christodoulos Mitrogiannis.
Facts
- Christodoulos Mitrogiannis defends his thesis 11 September, 09:15 at BMC, Lecture Hall B:41.
- Supervisors are Oscar Verho, Anders Karlén and Johan Wannberg, Uppsala University.
- Opponent at the dissertation is Alexander L. Satz, WuXi AppTec.
Contact
Christodoulos Mitrogiannis, PhD student
Department of Medicinal Chemistry
Christodoulos.Mitrogiannis@ilk.uu.se
text: Magnus Alsne, photo: Mikael Wallerstedt