Subcellular Definition of Accumulation in Escherichia coli

About This Grant

PROJECT SUMMARY Modern medicine's greatest pharmaceutical achievement has been the development of antibiotics, which revolutionized healthcare by enabling complex surgical procedures with substantially reduced infection risks. However, we now face an impending medical catastrophe as antimicrobial resistance threatens to usher in an era where these life-saving drugs become ineffective. Throughout history, discovering compounds effective against double-membrane bacterial pathogens has presented significantly greater challenges than targeting single-membrane Gram-positive organisms. This difficulty stems from the distinctive asymmetric outer barrier that double-membrane bacteria possess alongside their inner cellular boundary. Since most antimicrobial targets lie beyond this outer barrier, therapeutic compounds must successfully traverse it to exert their effects. Unfortunately, this outer structure demonstrates exceptional efficiency at preventing small molecule passage, presenting a formidable obstacle for researchers. The initial golden period of antimicrobial discovery capitalized on naturally occurring compounds that could be easily identified through conventional screening approaches. However, these traditional methods have yielded diminishing returns over recent decades, making new discoveries increasingly elusive. The future of antimicrobial development may be transformed by our expanding repositories of protein, genetic, and metabolic information, which could unveil promising therapeutic targets. Both academic institutions and pharmaceutical companies might harness these datasets to engineer small molecule therapeutics with enhanced potency and selectivity. To achieve this goal, we seek to formulate foundational principles that define the molecular characteristics governing cellular penetration in bacteria, similar to Lipinski's Rule of Five framework.