Deep learning-enabled protein design for targeted depletion of antibiotic resistant bacterial pathogens

About This Grant

Proteolysis-targeting chimeras (PROTACs) and Lysosome-targeting chimeras (LYTACs) have emerged as novel and effective therapeutic modalities that leverage targeted protein degradation (TPD) to eliminate disease-associated proteins. However, the preclinical and clinical development of TPD-based therapeutics has largely focused on malignant diseases, where bifunctional chimeric molecules have demonstrated the potential to target and degrade classically “undruggable” proteins. Here, we propose to design and extend the application of such bifunctional chimeric molecules to another class of difficult therapeutic targets, namely the antibiotic-resistant bacterial pathogens. As resistance to frontline antibiotic therapies continues to threaten our ability to combat many infectious organisms, there is a critical need for novel approaches that complement or bypass the traditional direct-acting antibiotics. Our central hypothesis is that rationally designed bacterial targeting chimeras (BacTACs), which specifically bind to a bacterial pathogen of interest and simultaneously engage host immune receptors, can enhance immune-mediated bactericidal activity toward the organism of interest. To achieve this, we will leverage our cutting-edge tools in deep learning-based protein design to generate high-affinity binders to both bacterial surface proteins and key host immune receptors, and then fuse them to create chimeric proteins capable of redirecting immune responses for rapid clearance of the infectious bacterial threats. Specifically, we will pursue the following aims to develop and characterize such BacTACs: In Aim 1, we will design high-affinity binders to surface-accessible proteins of Acinetobacter baumannii and Staphylococcus aureus; in Aim 2, we will develop and characterize designed proteins that engage phagocyte immune receptors; and in Aim 3, we will assess the efficacy of custom-designed BacTACs in tissue culture and murine models of bacterial infection. The validation of designed BacTACs will be conducted using the antibiotic-resistant strains of A. baumannii and S. aureus. The proposed approach to reprogram and redirect immune responses for targeting antibiotic-resistant pathogens addresses several resistance-related and efficacy-related limitations of traditional direct-acting antibiotics. Together, the design methods and BacTACs developed here will provide the basis for a new orthogonal modality to target antibiotic-resistant pathogens.