![]() Herein we provide an overview of emerging insights into this problem and outline a general approach to addressing it using prospective analysis of chemical libraries for the ability of compounds to accumulate in Gram-negative bacteria. As a result of these challenges, intensive screening campaigns have led to few successes, highlighting the need for new approaches to identify regions of chemical space that are specifically relevant to antibacterial drug discovery. Second, chemical libraries currently used in drug discovery contain few compounds that can penetrate Gram-negative bacteria. First, these bacteria are protected from a variety of structurally diverse drugs by a low-permeability barrier composed of two membranes with distinct permeability properties, in addition to active drug efflux, making this cell envelope impermeable to most compounds. ![]() In particular, Gram-negative pathogens present both biological and chemical challenges that hinder the discovery of new antibacterial drugs. We live in the era of antibiotic resistance, and this problem will progressively worsen if no new solutions emerge.
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