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Dr. Lejla Imamovic
Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Denmark
Title of the talk: Collateral sensitivity networks enable targeted therapeutic strategies against drug resistance
Drug resistance development is an inevitable, frequent consequence of chemotherapy that limits our ability to treat infectious disease. We established the direct link between drug resistance and increased (collateral) sensitivity of drug resistant strain of Escherichia coli. Exploring the negative side effect of drug selection processes that maintain the drug effectiveness could have a great utility in clinical treatments of chronic infections. Yet, the treatment strategies that incorporating critical vulnerabilities induced by antimicrobial resistance evolution (collateral sensitivity) are lacking. Thus, our aim was to underline complex networks of collateral sensitivity for Pseudomonas aeruginosa that can be employed for drug treatment to sustainably cycle drugs while selecting against resistance.
We performed experimental evolution in for P. aeruginosa PAO1 and 5 DK2 strains. Antibiotic resistant strains were selected during 10-day passage supplemented with clinically relevant antibiotics. P.aeruginosa drug resistance development to 24 clinically relevant drugs had a profound effect on drug susceptibility profiles. The majority of resistant strains (75%) were collaterally sensitive to at least one antibiotic. Based on these findings we identified complex networks of collateral sensitivity that can be employed for drug treatment to sustainably cycle drugs while selecting against resistance (collateral sensitivity cycling). To underline the genetic basis for collateral sensitivity and resistance, genomes of resistant strain were sequenced on a MiSeq platform. The genomic changes forcing the bacterial responses were detected in genes associated with drug susceptibilities commonly observed in clinics, including ampC, ampD, fusA1, gyrA, gyrB, mexB, and pmrB.
Understanding how the current therapeutics may change upon subsequent side effects due to resistance development are important to possible prolonging the life-span of anti-pseudomonal drugs. The drug application based on collateral sensitivities involves might integrating several factors important in the treatment of chronic infections, such as 1) presence of heterogeneous population, 2) immunomodulatory properties 3) polymicrobial infections. In addition, identifying the genetic link to drug resistance has a high impotence in treatment of long-term chronic infections that would allow to build targeted treatment for resistant populations.
Lejla Imamovic obtained her graduate studies at University of Sarajevo in Bosnia-Hercegovina and Master Degree at University of Hohenheim in Germany. She completed her PhD in Environmental Microbiology and Biotechnology from University of Barcelona in Spain in 2011. For her postdoctoral studies she worked at the Department for Systems Biology at Technical University of Denmark. Dr Imamovic is currently Research Scientist at Novo Nordisk Foundation Center for Biosustainability at Technical University of Denmark. Her main research interests include antibiotic resistance, horizontal gene transfer and functional and viral metagenomics.