Adaptive resistance mechanisms of Gram negative bacteria of the ESKAPE Group

Research Group PD Dr. Baharak Babouee Flury

Our research focuses on the in vitro and in vivo resistance development/adaptation of Gram of negative bacteria in response to antibiotic exposure. We investigate their resistance mechanisms in collaboration with researchers from external institutions (ETH, EMBL, Empa) and using various approaches, e.g.

  • Genomics
  • Transcriptomics
  • Proteomics
  • Genome editing (cloning, Crispr/Cas9)
  • Inhibition Assays

Current research activities

Resistance mechanisms of E. coli and P. aeruginosa from Tanzania

This study investigates antimicrobial resistance mechanisms of E.coli and P. aeruginosa isolated from patients with urinary tract infections or surgical site infections. The samples are collected from patients at St. Francis Referral Hospital in Ifakara, Tanzania. The study aims to close knowledge gaps by helping to define the resistance epidemiology and mechanisms for the above mentioned pathogens in Tanzania. It is intended to help improve infection control on site and serve as a guide for physicians in their choice of antimicrobial treatment. It is a large longitudinal study that also investigates risk factors for the selection of antibiotic resistance. The study is being conducted in cooperation with the Swiss Tropical Institute and is in the phase of patient/sample recruitment.

Resistance development of E. coli under challenge with Delafloxacin and Ciprofloxacin

The U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), have approved Delafloxacin (DLX), a novel dual-acting non-zwitterionic fluoroquinolone, for the treatment of acute bacterial infections of the skin and skin structures (ABSSSI) and community-acquired bacterial pneumonia (CPA) in adults, caused by susceptible strains. DLX has excellent activity against Gram-positive organisms and anaerobes and similar MICs as ciprofloxacin (CIP) against Gram-negative bacteria. DLX has anionic character at neutral pH (~7-7.4) and is mainly uncharged at slightly acidic pH, which differs from other fluoroquinolones (e.g. ciprofloxacin, levofloxacin, moxifloxacin), which are present as cations at acidic pH and mainly as zwitterions at higher values and whose activity decreases in the acidic environment. This property could explain the greatly improved efficacy of DLX in acidic environments, as the non-ionized form is considered better diffusible by biological membranes.

Unlike CIP, DLX shows a similar affinity for both enzymes, topoisomerase IV and DNA gyrase, in both Gram-positive and Gram-negative bacteria. In addition, inhibition of the efflux system potentiates the activity of DLX against E. coli in biofilms and pathogenic E. coli strains in the stationary phase.

The standard conditions for in vitro antibiotic susceptibility tests do not always reflect the micro-environmental conditions of the source of infection. The pH of purulent abscess fluids ranges from 5.5 to 7.2. Same applies to biofilms - including those of E. coli - for which pH values between 3.5 and 6.0 have been documented. Given the importance of the microenvironment of the source of infection, we want to determine the development of resistance of E. coli to DLX and CIP in an acidic and neutral environment.

Resistance mechanisms of P. aeruginosa to Ceftazidim-avibactam

In this study, which is conducted in collaboration with EMBL Heidelberg, ETH-D BSSE and Empa (Materials Science and Technology), we decoded the previously unknown resistance mechanisms of P. aeruginosa to ceftazidime avibactam (CZA), a novel antibiotic, using a multi-omics (genomics, transcriptomics, proteomics) approach. Resistant derivatives were generated by a multi-step resistance selection for CZA and meropenem and cross-resistance was evaluated. This study is in phase of genome editing, where we are implementing interesting mutations that we found in whole-genome sequencing (compared to the transcriptome and proteome) into the parenteral strains.

 

Collaborations

As part of our research projects, we are currently working together with the following partners:

  • European Molecular Biology Laboratory (EMBL), Heidelberg
  • Swiss Federal Laboratories for Materials Science and Technology (Empa), Biointerfaces

KSSG research database

On the research database of the KSSG you will find further information regarding our projects and publications.