Breaking resistance of pathogenic bacteria by chemical dysregulation

ongoing

Antibiotic resistant bacteria are on the rise and could trigger the next global pandemic. For some pathogens no treatment options are left, leading to steadily increasing death tolls. The limited scope of bacterial targets, all essential for growth, has favored resistance build-up whilst also being ineffective against non-growing persister cells. To overcome this threat, innovative concepts are required to effectively and sustainably kill bacteria via unprecedented mechanisms. My team and I tackle this challenge by deliberately going beyond established modes of action (MoA). To achieve this, we present breakingBAC: a three-tiered chemical strategy to dysregulate bacterial physiology. First, we will develop small molecule activators of crucial bacterial hydrolases to deregulate the degradation of proteins, leading to devastating physiological effects. Although enzyme stimulation has several advantages over inhibition, this concept is still in its infancy. We thus showcase principles of activator discovery and demonstrate their potency against diverse pathogens. Second, we recently discovered the complexation of free cellular heme by antibiotic isonitriles leading to a dysregulation of porphyrin biosynthesis and a corresponding induction of oxidative stress. Although these isonitriles are too large to access protein bound heme, we will tailor their structure to additionally target hemedependent enzymes of the stress response. The aim is to develop molecules bearing a dual MoA: a) stress induction and b) inhibition of stress response. Third, we will combine our learnings to create bifunctional compounds consisting of a hyperactivating protease recruiter linked to a bait which delivers the large class of essential heme-dependent enzymes for proteolysis. As these protein degraders are hyperactive, catalytic in nature, and specific for bacterial proteases, we anticipate potent antibiotic effects combined with low resistance frequencies and lack of human toxicity.