Uppsala University: Anders Karlén coordinates the combat against the invisible enemy
According to a study published in The Lancet, an estimated 1.3 million people died in 2019 because of infections caused by resistant bacteria. This makes it one of the world’s deadliest diseases and the curve is rising sharply. Nevertheless, the fight against accelerating antibiotic resistance is facing difficulties finding a place on society’s agenda, and the question is what it will take to bring about the mobilisation necessary to reverse this negative trend?
“This problem is global and several EU countries are already severely affected. In Sweden, still relatively spared, most people only perceive the threat along the horizon, and this is one of our major challenges: As long as disaster does not strike with full force, many prefer to look elsewhere. However, the fact that modern healthcare depends on effective antibiotics means that increasing resistance threatens the foundations of critical medical care,” states Anders Karlén, Professor of Computer-Aided Drug Design.
To find the last time that science discovered a new class of antibiotics that actually reached the clinic, we have to search as far back as 1984. At roughly the same time, the newly recruited PhD student Anders Karlén began to build new molecules and study their potential properties in the computer. Computational chemistry was still in its infancy, and equipped with a terminal and a modem in Uppsala’s Biomedical Centre, Anders worked late evenings using a computer based in Lund – office hours did not provide enough capacity for advanced calculations.
“Being one of the earliest links in the pharmaceutical chain, our task is to identify promising chemical starting points for the development of new drugs. In the case of antibiotics, we are looking for potential points of attack within the bacteria, and for the molecules that can kill bacteria. Normally we must design, synthesize and test several hundred compounds before we – if everything goes well – identify a substance worth developing further. Fortunately the tools of today have completely different capabilities than when I first started my research career and we can now do things far more efficiently.”
Over the years, the problems caused by resistant bacteria have grown far more complex than one single field of science could possibly solve, making interdisciplinary collaborations essential. Since 2016 Anders Karlén has been engaged on the board of the Uppsala Antibiotic Center, a PhD school where Uppsala University’s three disciplinary domains are laying the foundations for future antibiotic research. Two years earlier, Anders shouldered the task of coordinating ENABLE, the IMI-funded flagship project that united fifty European universities and biotech and pharmaceutical companies working together on the frontline in the search for new antibiotics.
“We received 85 million euros and just over seven years to drive the development of a number of antibiotic candidates and bring at least one of them through a clinical phase 1 study. We aimed high and the role came with many challenges, but above all it was extremely exciting to be part of something that I thought never would come my way. When ENABLE crossed the finish line in the autumn of 2021, we had met all goals with a margin and Uppsala had proven that we have the experience, skills and contacts required to take the driver’s seat in collaborations of this size.”
The success of ENABLE has made an impression, and in 2019 Uppsala University won another big call: COMBINE, a new pan-European IMI initiative that, with Anders Karlén once more at the wheel, supports eight projects that are part of the AMR Accelerator initiative, aiming to develop new drugs against tuberculosis and infections caused by Gram-negative bacteria. Also in Sweden, focus turned towards Uppsala’s Faculty of Pharmacy, and just days before ENABLE was closed, the Swedish Research Council announced a grant of SEK 25 million to ENABLE-2, an international platform that, with the hub at Uppsala University and coordinated by Anders Karlén, provides support to promising projects in the early stages of antibacterial drug development.
At the Uppsala Biomedical Centre lab
In action at the Uppsala Biomedical Centre lab
“It is a phase where the need for project support is enormous, and the Swedish Research Council’s confidence gives us room to continue building a model we have already developed. An initial call generated several highy interesting proposals, and an independent committee has selected five promising projects that we are working with throughout 2022, which is as far as our initial funding goes. What will happen after the turn of the year is uncertain, but we hope for continued funding from the Swedish Research Council and are also in talks with potential partners in both Sweden and Europe, and everyone seems to agree that a pipeline into the system is needed if we are to expect anything to come out at the end.”
Anders Karlén knows what he is talking about. After twenty years of fruitless search for a substance with sufficient antibacterial and drug-like properties, his research team has succeeded in identifying a molecule that attacks two out of the four gram-negative bacterial strains defined by WHO as being among the greatest threats to our planet. The project received support via ENABLE and today its development continues within the framework of ENABLE-2. The results give every reason for optimism; however, the future of the project hangs on a fragile thread.
“In the best of worlds, we’ll manage to bring our compunds into the next phase and the opportunities that open up there. If not, the risk is obvious that our work will end up in limbo, since it is almost impossible to find funding for drug development in the field of antibiotics, which for me confirms the importance of targeted initiatives like ENABLE-2. Equally necessary is that we raise the pharmaceutical industry’s interest in developing new antibiotics. I know that discussions are taking place about possible financial incentives and that several interesting ideas are on the table. I myself have turned 63, and if I only maintain my health, my hope is to take the research of our team as close to a new antibiotic as possible, but resistant bacteria are without a doubt a challenge that the world will have to deal with long after I leave the laboratory.”