Defining new chemical space for drug penetration into Gram-negative bacteria
Autor: | Vincent Bonifay, Shibin Zhao, Helen I. Zgurskaya, Jitender Mehla, Justyna W. Adamiak, Derek S. Tan |
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Rok vydání: | 2020 |
Předmět: |
Drug
Cell Membrane Permeability Gram-negative bacteria Chemistry Pharmaceutical media_common.quotation_subject Porins Drug resistance Article Small Molecule Libraries Structure-Activity Relationship 03 medical and health sciences Antibiotic resistance Drug Resistance Multiple Bacterial Drug Discovery Gram-Negative Bacteria Humans Structure–activity relationship Computer Simulation Molecular Biology 030304 developmental biology media_common 0303 health sciences Models Statistical biology Drug discovery Cheminformatics Cell Membrane 030302 biochemistry & molecular biology Biological Transport Cell Biology biology.organism_classification Chemical space Anti-Bacterial Agents Biochemical engineering Efflux |
Zdroj: | Nat Chem Biol |
ISSN: | 1552-4469 1552-4450 |
Popis: | We live in the era of antibiotic resistance, and this problem will progressively worsen if no new solutions emerge. In particular, Gram-negative pathogens present both biological and chemical challenges that hinder the discovery of new antibacterial drugs. 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. Second, chemical libraries currently used in drug discovery contain few compounds that can penetrate 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. 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. The overall goal is to develop robust cheminformatic tools to predict Gram-negative permeation and efflux, which can then be used to guide medicinal chemistry campaigns and the design of antibacterial discovery libraries. |
Databáze: | OpenAIRE |
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