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FRIMEDBIO-Fri med.,helse,biol

Disentangling penicillin resistance and compensatory adaption in pneumococci by combining genomics and molecular microbiology.

Alternative title: Å forene genomikk med molekylærbiologi for å forklare penicillinresistens og kompensatoriske tilpasninger hos pneumokokker.

Awarded: NOK 12.0 mill.

Pneumococci (Streptococcus pneumoniae) is a major human pathogen. This bacterium causes for example pneumonia, ear infection, bacteremia, and meningitis. Penicillin is the antibiotic of choice when treating pneumococcal infections. However, the quick rise of resistant isolates challenges healthcare systems, which are running out of treatment options. This bacterium is found on WHO’s list of species that must be prioritised in the efforts to develop new antibiotics and other antimicrobial strategies. We know that penicillin resistance comes with a fitness cost to the pneumococci, i.e. the bacteria often need to change some unknown genes in order to allow the functionality of the penicillin resistance genes. In this project we will identify these unknown genes, whose change allow high penicillin resistance. We are going to sequence all the genes in more than 1000 pneumococcal isolates collected by the Norwegian Institute of Public Health. They include both sensitive and resistant isolates. By combining bioinformatics and molecular biology we will try to find and confirm experimentally the compensatory mutations required for penicillin resistance to occur in pneumococci. When we have identified these genes, we can exploit this information to our advantage. For example, if one could find a compound that inhibits the function of a gene required for high level penicillin resistance, this compound could re-sensitize pneumococci to penicillins. By combining this new compound with existing penicillins, we could keep our penicillin antibiotics relevant as treatment options in the future. Another important goal of the project is to map the origin, spread and frequency of penicillin resistant pneumococci in Norway.

Pneumococci are major contributors to morbidity and mortality world-wide. The antibiotics of choice for treatment of pneumococcal infections are beta-lactams (including penicillin). However, their superior role as efficient drugs is fading in concert with the accelerating spread of beta-lactam resistance genes. Interestingly, beta-lactam resistant pneumococci must employ less efficient cell-wall synthesizing enzymes (low-affinity PBPs) which impose them a fitness cost that has great therapeutically potential. To become successful resistant clones, they acquire compensating mutations re-establishing their fitness. The proposed project will combine genome-wide association and epistasis analyses with molecular biology providing new knowledge on the mechanisms used by pneumococci to alleviate the fitness cost of being resistant to beta-lactam antibiotics. This will open the way for research aimed at generating more effective beta-lactams that are less prone to resistance development, keeping beta-lactams relevant as effective drugs in the future. By identifying specific pathways, and enzymatic functions required for relieving the fitness cost, it will be possible to screen for small molecules targeting these compensatory mechanisms that can be used in combination with existing beta-lactam antibiotics to sensitize already resistant strains. In our search for fitness cost mutations, we will genome sequence 1500 uncharacterized isolates from Norwegian patients and healthy carriers. This will also answer questions related to the spread and evolution of pneumococcal beta-lactam resistance in Norway, which is largely unknown. It will enhance our ability to trace resistant strains and give knowledge which can help implement strategies to slow the spread of resistant pneumococci in the population.

Funding scheme:

FRIMEDBIO-Fri med.,helse,biol