Development of phenylalanine amides and piperidine-4-carboxamides with antibacterial activity against drug-resistant mycobacteria - Synthetic derivatization, antimycobacterial evaluation and pharmacokinetic characterization

• Applicant: Dr. Adrian Richter
• Subject Area: Pharmacy ; Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology ; Organic Molecular Chemistry - Synthesis and Characterisation
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 432291016

The research project aims to develop two classes of antibacterial compounds with activity against drug-resistant mycobacterial species. Non-tuberculous mycobacteria, such as Mycobacterium abscessus and Mycobacterium avium, but also Mycobacterium tuberculosis (with acquired drug resistance), cause severe pulmonary infections that are difficult to treat due to their pronounced insensitivity to antibiotics. Therefore, the research project aims to advance the development of drug candidates that combine high antibacterial activity against mycobacteria with good pharmacokinetic properties through the interdisciplinary use of methods from medicinal chemistry and microbiology. The compounds belong to the piperidine-4-carboxamide and phenylalanine amide classes. Both classes of compounds have already been characterised in terms of their activity and structure-activity relationships, as evidenced by several publications by the applicant. The phenylalaninamides are inhibitors of mycobacterial RNA polymerase, while the piperidine-4-carboxamides act by inhibiting gyrase. The most active derivatives of both classes achieve minimum inhibitory concentrations between 0.4 and 0.8 µM against Mycobacterium abscessus and are also active against Mycobacterium tuberculosis. As part of a DFG-funded project, synthesis routes for both classes of compounds were established and the compounds were derivatised, providing information on structure-activity relationships. Despite promising antibacterial activity, both classes of compounds show insufficient bioavailability in vivo, probably due to rapid metabolic inactivation. The follow-up proposal addresses this problem: the mechanism of metabolic inactivation will be elucidated by analysing the degradation products in order to allow targeted optimisation of the compounds. New analogues will be prepared using different derivatisation strategies and their metabolic stability will be investigated in vitro and in vivo. An important component of the research project is the microbiological characterisation of the new drug molecules against pathogenic mycobacteria. For this purpose, the working group has an established arsenal of methods for determining the minimum inhibitory concentration, bactericidal activity and testing against bacteria during infection in macrophages. However, the aim of the project is to develop new innovative methods to ensure comprehensive in vitro characterisation of drug candidates. This will include the development of a fluorescence-based bactericidal assay and the investigation of drug sensitivity in artificial caseum.

• DFG Programme: Research Grants
• International Connection: USA
• Cooperation Partners: Professorin Elizabeth Campbell, Ph.D.; Professor Thomas Dick, Ph.D.