title: Progress against Escherichia coli with the Oxazolidinone Class of Antibacterials: Test Case for a General Approach To Improving Whole-Cell Gram-Negative Activity.
abstract: Novel antibacterials with activity against the Gram-negative bacteria associated with nosocomial infections, including Escherichia coli and other Enterobacteriaceae, are urgently needed due to the increasing prevalence of multidrug-resistant strains. A major obstacle that has stalled progress on nearly all small-molecule classes with potential for activity against these species has been achieving sufficient whole-cell activity, a difficult challenge due to the formidable outer membrane and efflux barriers intrinsic to these species. Using a set of compound design principles derived from available information relating physicochemical properties to Gram-negative entry or activity, we synthesized and evaluated a focused library of oxazolidinone analogues, a currently narrow spectrum class of antibacterials active only against Gram-positive bacteria. In this series, we have explored the effectiveness for improving Gram-negative activity by identifying and combining beneficial structural modifications in the C-ring region. We have found polar and/or charge-carrying modifications that, when combined in hybrid C-ring analogues, appear to largely overcome the efflux and/or permeability barriers, resulting in improved Gram-negative activity. In particular, those analogues least effected by efflux and the permeation barrier had significant zwitterionic character.
authors.affiliation: 64 Berkshire Street, Apartment 3, Cambridge, Massachusetts 02141, United States.
authors.forename: Khuloud
authors.initials: K
authors.lastname: Takrouri
authors.affiliation: 9709 Bedder Stone Place, Bristow, Virginia 20136, United States.
authors.forename: Harold D
authors.initials: HD
authors.lastname: Cooper
authors.affiliation: Department of Chemistry and Chemical Biology, Northeastern University , Boston, Massachusetts 02115, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Spaulding
authors.affiliation: Department of Pharmacy and Health Systems Sciences, School of Pharmacy, Northeastern University , Boston, Massachusetts 02115, United States.
authors.forename: Paola
authors.initials: P
authors.lastname: Zucchi
authors.affiliation: Department of Chemistry and Chemical Biology, Northeastern University , Boston, Massachusetts 02115, United States.
authors.forename: Bilyana
authors.initials: B
authors.lastname: Koleva
authors.affiliation: 99 Spruce Street, Middleboro, Massachusetts 02346, United States.
authors.forename: Dillon C
authors.initials: DC
authors.lastname: Cleary
authors.affiliation: Department of Chemistry and Chemical Biology, Northeastern University , Boston, Massachusetts 02115, United States.
authors.forename: Westley
authors.initials: W
authors.lastname: Tear
authors.affiliation: Department of Chemistry and Chemical Biology, Northeastern University , Boston, Massachusetts 02115, United States.
authors.forename: Penny J
authors.initials: PJ
authors.lastname: Beuning
authors.affiliation: Department of Pharmacy and Health Systems Sciences, School of Pharmacy, Northeastern University , Boston, Massachusetts 02115, United States.
authors.forename: Elizabeth B
authors.initials: EB
authors.lastname: Hirsch
authors.affiliation: Revolution Medicines , 700 Saginaw Drive, Redwood City, California 94063, United States.
authors.forename: James B
authors.initials: JB
authors.lastname: Aggen
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects* / Q000502:physiology; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000382:microbiology; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy / Q000382:microbiology; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D023303:Oxazolidinones / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D023303:Oxazolidinones
keywords: Gram-negative; efflux pump; outer membrane permeability; oxazolidinones; porins