Fellow: Vincent Trebosc
Supervisor: Dr. Christian Kemmer (BioVersys AG)
Co-supervisor: Prof. Dirk Bumann (University of Basel)
BioVersys follows the approach of inhibiting global or local transcriptional regulators of resistance gene expression. Our TRIC (Transcriptional Regulator Inhibiting Compounds) technology platform allows for the identification of target specific, non-cytotoxic and non-antibacterial small molecules that potentiate the activity of antibiotics. The combinatorial application of BioVersys` TRIC adjuvant compounds with existing antibiotics has been shown to allow for killing of even extensively resistant pathogens at clinically relevant doses of the antibiotic.
We designed a novel gene knockout platform, which does not require any antibiotic resistance marker, to be able to do gene deletions in gram negative multidrug resistant clinical isolates of the ESKAPE pathogens. We applied this system to validate the transcriptional regulator AdeR, suggested to be essential in the tigecycline resistance pathway of Acinetobacter baumannii, as a putative drug target. We confirmed the important role of AdeR in conferring tigecycline resistance by upregulation of the efflux pump AdeABC. However, we demonstrated that targeting AdeR is not sufficient to switch-off tigecycline resistance in clinical isolates and to rejuvenate the activity of this antibiotic. Our work clearly devalidated AdeR as a potential drug target.
Our developed gene knockout technology is now routinely applied in MDR isolates to evaluate a selection of transcriptional regulators that are involved in the regulation of diverse antibiotic resistance pathways in different pathogens of the ESKAPE-group. This approach results in a rapid evaluation of putative drug targets that will be, after successful validation, incorporated into the TRIC technology platform of BioVersys.
Trebosc, V. et al. A Novel Genome-Editing Platform for Drug-Resistant Acinetobacter baumannii Reveals an AdeR-Unrelated Tigecycline Resistance Mechanism. Antimicrob. Agents Chemother. 60, 7263–7271 (2016).