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Progress Towards Addressing Gram Negative Bacterial Resistance
Author(s) -
Koleva Bilya.,
Takrouri Khuloud,
Cooper Harold D.,
Spaulding Andrew,
Zucchi Paola,
Cleary Dillon,
Tear Wesley,
Hirsch Elizabeth B.,
Aggen James B.,
Beuning Penny J.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.853.13
Subject(s) - efflux , linezolid , antibiotics , bacteria , antibiotic resistance , microbiology and biotechnology , staphylococcus aureus , context (archaeology) , gram negative bacteria , bacterial outer membrane , biology , chemistry , escherichia coli , vancomycin , biochemistry , gene , paleontology , genetics
Multidrug antibiotic resistance poses an increasingly urgent threat to global health and the world economies. Among antibiotic resistant species, gram negative bacteria present the utmost urgency as they have become resistant to nearly all available treatment options. Combating antibacterial resistance should include continuous introduction of new antibiotic classes; however over the last 40 years there has been a void in antibiotic drug discovery. Extending the spectrum of activities of current classes of antibiotics is another approach. The oxazolidinones are a class of antibiotics that work by interfering with protein translation and are mainly active against gram‐positive bacteria. Linezolid, marketed under the trade name Zyvox®, was the first FDA‐approved oxazolidinone for the treatment of pathogenic gram‐positive bacteria. One focus of this work is to optimize the properties of oxazolidinones in order to penetrate the lipopolysaccharide layer of gram‐negative bacteria while maintaining their target potency. The rational lead optimization campaign based on the linezolid scaffold involves keeping a low molecular weight (MW <400 Da), and high polarity (clog D <1) to allow passage through the porins and to be able to escape the bacterial efflux pumps. A focused library of oxazolidinone analogs was synthesized and evaluated for activity in a panel of wild‐type and outer membrane‐ and or efflux pump‐compromised Escherichia coli and Staphylococcus aureus . Several C‐ring modification analogs offered moderate activity against gram negative bacteria and seem to improve membrane permeability and evasion of the efflux pumps. A subset of these compounds was tested in the context of an in vitro transcription and translation assay and most were found to be comparable to linezolid in terms of efficacy.