An Accumulation Rulebook & Vulnerability Atlas for Klebsiella spp.

One of the biggest challenges in the development of new antibiotics is finding compounds that accumulate in sufficient concentration within bacterial cells to exert a growth inhibitory effect. A second major challenge is the paucity of new, functionally validated and chemically tractable targets, which results in a lack of novelty in the antibiotic pipeline. We will use deep exploration of chemical space and computational approaches to define molecular fingerprints and learn the chemical rules of cellular accumulation of small molecules. In parallel, we will discover and functionally validate chemically- tractable protein targets, generating a proteome-scale atlas of drug target vulnerabilities. Drawing insight from our accumulation rulebook and vulnerability atlas, we will know which targets to hit, where to hit them, and how to design molecules hitting these sites to accumulate at the target.We will: develop a high-throughput accumulation measurement platform; generate an open-data and AI/ML model for active learning of accumulating compounds; determine the chemical 'rules of accumulation' in Klebsiella to enable rational design of high-accumulating antibacterials; provide validated protocols, data, models and an accumulation compound set to facilitate studies in other bacteria by the community; identify and validate new chemically- tractable protein antibiotic targets in Klebsiella.