On June 16th, 2017 Vincent Trebosc successfully defended his thesis at Bioversys!
“Adjuvant drug therapy to overcome antibiotic resistances: drug target evaluation in multidrug resistant pathogens”
Antimicrobial resistance is a serious threat for public health worldwide. The risk to enter a post-antibiotic era has been raised due to the emergence of pathogens resistant to most of available antibiotics. Beside research on novel antibiotics, innovative approaches may provide another solution to combat infections. One of the innovative approach resides in adjuvant therapies that have the capability to revert antibiotic resistances. This approach has been successfully applied during decades with β-lactams inhibitors but never expanded to other antibiotics. My work aimed to investigate the adjuvant therapy approach in Acinetobacter baumannii and Mycobacterium tuberculosis, which are two pathogens of great importance with constantly increasing drug resistance rates.
The development of a genome engineering method allowed us to characterize the different mechanisms employed by A. baumannii to resist the antibacterial action of tigecycline and colistin antibiotics during patient treatment. Overall, we showed that the mechanisms employed to resist the action of a specific antibiotic may be diverse due to the treatment history of the individual clinical strains. This impairs the development of adjuvant drug to overcome tigecycline and colistin resistances in A. baumannii and it implies a careful evaluation of drug target relevance before to develop inhibitors that are specific of one resistance pathway. Nevertheless, our data highlight phosphoethanolamine transferase enzymes as attractive targets to restore polymyxin sensitivity in A. baumannii.
Furthermore, on M. tuberculosis, we successfully demonstrated that adjuvant approaches have the potential to overcome antibiotic resistance. By designing a synthetic mammalian gene regulation system, we assisted the development of EthR2 inhibitory compounds that boost the newly discovered M. tuberculosis ethionamide bioactivation pathway. These compounds not only revert ethionamide resistance in MDR M. tuberculosis, but also boost the ethionamide efficacy in drug susceptible strains, rendering ethionamide into a more potent antibiotic. These adjuvant compounds are very promising chemical entities and they are currently in pre-clinical development.
The research performed in this thesis demonstrated that special attention should be paid to drug target evaluation. The non-essential nature of these drug targets promotes a higher diversity and heterogeneity and careful target validation is required before starting a drug development program. However, the successful development of ethionamide boosting compounds that also switch off bacterial resistance traits demonstrates the potential of novel therapeutic adjuvant approaches.