New antibiotics might just weaken bacteria

UEF Bulletin 2017

If we can’t kill bacteria, weakening them may be an option. Researchers seek to tackle the global threat of antibiotic resistance with a new approach to antibacterial drugs.  

Text Ulla Kaltiala Photos Raija Törrönen

The price the world is paying for decades of liberal use – and misuse – of antibiotics is that a growing number of bacteria are now resistant to antibiotics. Gram-negative bacteria, which protect themselves with a double membrane, are especially prone to becoming resistant. In addition, by targeting vital processes in the bacterial cell, conventional antibiotics themselves put pressure on bacteria to mutate and develop resistant strains.

An alternative approach is to weaken the bacteria instead of trying to kill them. This could give the host immune system a better chance to fight the infection – or boost the impact of conventional antibiotics as a synergistic treatment, according to researchers in the INTEGRATE consortium. Funded by the EU Horizon 2020 Programme, INTEGRATE is a multidisciplinary Marie Curie Educational Training Network aiming to develop new types of drugs against Gram-negative bacteria. The project involves ten partners from academia and industry hosting eleven early stage researchers.

Escherichia Coli or E. Coli is one bacterium of interest in the project. It’s a normal part of gut flora, but some strains cause infections varying from urinary tract infections to pneumonia and sepsis. “Our aim is to decrease the fitness of Gram-negative bacteria by inhibiting the ClpP protease, the function of which is directly related to their virulence. The structure of ClpP in E. Coli is well known, making it a good starting point,” says Early Stage Researcher Carlos Moreno Cinos ( pictured above right).  

His job is to design, synthesise and characterise new molecules that can modulate ClpP. His PhD position is in the Medicinal Chemistry Group led by Professor Koen Augustyns at the University of Antwerp, but he came to UEF’s Kuopio Campus for a secondment in computer-aided drug design, supervised by Professor Antti Poso. “Computer modelling helps to predict the interaction of the molecules with the target, to optimise their structure and to screen for new molecules,” says Moreno Cinos, summing up the benefits.

“Hit compounds – molecules that actually affect the target – are more likely to be found with the help of virtual drug design,” adds Early Stage Researcher Prasanthi Medarametla (pictured above left).

Medarametla works in Kuopio within the work package of computer-aided drug design, hit finding and optimisation led by Professor Poso. Her research evolves around LsrK kinase, an enzyme critical for bacterial communication and thus an attractive target for new anti-virulence drugs. She has built a virtual model of the kinase and is now testing selected molecules against it. “During my secondments in partner institutions I will learn to synthesise molecules in the lab and carry out biological assays. This will enable me to better evaluate the feasibility of virtual molecules in real life.”

 “It’s much easier to collaborate with different research groups once you have hands-on experience of what they do,” Moreno Cinos says.  

Indeed, a central goal of the project is to expose the early stage researchers to all aspects of the antimicrobial discovery process. “Such expertise is valuable within the pharmaceutical industry and hard to get otherwise.”

 “Superbugs” are a global health threat

  • The spreading of antibiotic-resistant bacteria is one of the biggest threats to global health. Bacteria that are resistant to multiple antibiotics are sometimes referred to as “superbugs”.
  • Resistance occurs when bacteria change in the presence of antibiotics. As a result, antibiotics become ineffective and infections persist.
  • All antibiotics cause resistance, so new antibacterial agents are needed constantly. However, in the past few decades, their development has been lacking.
  • Some other factors accelerating the antibiotic resistance crisis include overuse of antibiotics in medicine and farming; patients using non-prescribed antibiotics or not finishing their antibiotic treatment; and poor infection control in hospitals.  
  • Resistant bacteria can circulate in human and animal populations, as well as through food, water and the environment.
  • Antibiotic resistance threatens the treatment of many infectious diseases, like urinary tract infections, pneumonia, tuberculosis and blood-stream infections, as well as the safety of cancer treatments and surgical operations.
  • Antibiotic resistance leads to longer hospital stays, higher medical costs and increased mortality.
  • Sources: WHO, European Medicines Agency