Development of ClpP-hijacking degraders of DNA gyrase as novel antibiotics

• Applicant: Dr. Aurélien Fleury Adié à Moumbock
• Subject Area: Pharmacy
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 562024096

Pathogenic microbes, including bacteria, fungi, protozoans, viruses, and helminths, are increasingly evolving mechanisms to resist the current range of marketed antimicrobials. This driven by genetic mutations, enzymatic mechanisms, and the widespread overuse of anti-infective agents. This resilience has led the World Health Organization (WHO) to classify antimicrobial resistance as a critical global public health threat, contributing to millions of deaths annually from bacterial infections alone. In response, there is a pressing need for novel antibiotics to combat the declining effectiveness of existing treatments against multidrug-resistant strains. A promising strategy involves bacterial proteolysis-targeting chimeras (BacPROTACs), bifunctional molecules that can selectively degrade essential bacterial proteins via the ATP-dependent caseinolytic (Clp) chaperone–protease complex proteolytic machinery. In general, PROTACs have an event-driven mechanism of action and are superior to occupancy-driven small-molecule inhibitors, due to their catalytic nature, higher potency, longer duration of action, reduced dosing frequency, higher selectivity, and reduced toxicity. Owing to their unique aforementioned properties, PROTACs could serve as long-acting standalone therapies to combat diverse forms of drug resistance. Several PROTACS are currently in clinical trials for various human malignancies, thus, highlighting the immense therapeutic potential of targeted protein degradation. Recent work by Clausen and colleagues has successfully demonstrated ClpC1/2-hijacking BacPROTACs, capable of inducing self-degradation of ClpC1 and ClpC2 in Mycobacterium tuberculosis, effectively targeting both antibiotic-sensitive and resistant strains. Building upon this foundation, the current project aims to computationally design, chemically synthesize, and biologically evaluate ClpP-hijacking degraders of DNA gyrase—an essential bacterial protein absent in humans, thus presenting an optimal target for antibiotic innovation. The proposed degraders will encompass three core components: a potent DNA gyrase ligand, a potent ClpP ligand, and a flexible linker to facilitate effective ClpP-gyrase interactions. Employing the non-pathogenic bacterium Escherichia coli as a model organism, this study will assess the efficacy of these degraders before advancing to pathogenic bacteria. By pursuing this innovative approach to antibiotic development, the project aspires to enhance the therapeutic repertoire in the ongoing battle against multidrug-resistant bacterial strains, underscoring the necessity of integrating cutting-edge Medicinal Chemistry, Chemical Biology, Biochemistry, and Microbiology.

• DFG Programme: WBP Position