Antibiotics are widely used to treat and prevent especially post-surgery bacterial infections. However, bacteria can eventually develop multiple mechanisms of resistance against antibiotics. Their most effective form of defense is biofilm, a complex community of bacteria. Biofilm communities require up to a thousand times higher doses of conventional antibiotics than single bacterial cells, and the treatment times need to be longer.
Approximately 80% of hospital-acquired infections are biofilm-related and many of them are caused by the bacterium Staphylococcus aureus, a highly dangerous pathogen.
"S. aureus is classified in the top-priority lists according to the World Health Organization. Currently, there are no approved antibiotics specifically targeting biofilm infections of S. aureus, so we urgently need new antibiotics for treating its resistant form," says Dr. Ghada Hassan, former PhD student at the Faculty of Pharmacy.
Student collaboration from coffee break to lab
To start tackling the worldwide problem, PhD students in the Faculty of Pharmacy designed, synthesized, and discovered a new class of antimicrobial compounds that can interfere with the biofilm formation of S. aureus. It is also able to kill nearly 99.9% of the bacterial biofilm cells.
How did this come about? Medicinal chemist Riccardo Provenzani answers that it took four PhD students and friends: microbiologist Paola San Martin Galindo, computational chemist Ashenafi Legehar, medicinal chemist Ghada Hassan, and himself, who were talking during a coffee break about their research projects and how the University of Helsinki is encouraging cooperation among different research groups for multidisciplinary studies.
The discussion went like this:
“Hey, what about starting a new project ourselves?” Ghada asked.
“If you have some untested compounds, I could expose bacteria to them,” Paola answered.
“I have some pyrimidines! According to the literature, they could be antibacterial,” Riccardo replied.
“Great! If Paola gets any hits, we could synthesize new ones.” Ghada said. “Ash, if we give you the structures, could you check information about possible targets and activities?”
“Sure! I’ll have a look.” Ashenafi replied.
So, they brought this idea to their supervisors, Professor Jari Yli-Kauhaluoma, Dr. Adyary Fallarero, and Dr. Henri Xhaard. After their approval, they started the project, shared their expertise, worked closely, and followed up their progress with regular meetings.
Guided by feedback from microbiological data and confirmed by the computational follow-up, they synthesized two sets of new compounds and identified three candidates, which were further evaluated and confirmed as agents with high antimicrobial and anti-biofilm activity against S. aureus.
“With a computational method we also compared our compounds to approximately 1.5 million compounds from public databases. The results showed that our anti-biofilm compounds are unique and no compound with closely related structure showed similar activity against S. aureus,” Ashenafi Legehar says.
“These findings represent a new door opened towards the development of a new class of anti-biofilm agents to face the high demand for antimicrobials nowadays. Thus, we encourage working in multidisciplinary teams,” Paola San Martin Galindo adds.
“This study holds promise as an early-stage drug discovery process and we hope that this inspires additional discoveries to combat antimicrobial resistance and superbugs,” Riccardo Provenzani concludes.
The research-track trainee Aleksi Kallio also joined the project and completed one of his trainings in the synthesis laboratories under the supervision of Riccardo and Ghada.
Reference:
Provenzani, R. et al. Multisubstituted pyrimidines effectively inhibit bacterial growth and biofilm formation of Staphylococcus aureus. Sci Rep 11, 7931, doi:10.1038/s41598-021-86852-5 (2021).
This project would not have been possible without the support from the Strategic Research Council at the Academy of Finland (SRC-SUDDEN, Project No. 320210), the Academy of Finland (Project No. 307464), the Jane and Aatos Erkko Foundation, and the Finnish Cultural Foundation.