title: Identification of a novel protein synthesis inhibitor active against gram-positive bacteria.
abstract: In an effort to identify novel antibacterial chemotypes, we performed a whole-cell screen for inhibitors of Staphylococcus aureus growth and pursued those compounds with previously uncharacterized antibacterial activity. This process resulted in the identification of a benzothiazolium salt, ABTZ-1, that displayed potent antibacterial activity against Gram-positive pathogens. Several clinically desirable qualities were demonstrated for ABTZ-1 including potent activity against multidrug-resistant clinical isolates of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococci (VRE), retention of this activity in human serum, and low hemolytic activity. The antibacterial activity of ABTZ-1 was attributed to its inhibition of bacterial translation, as this compound prevented the incorporation of [³⁵S]methionine into S. aureus proteins, and ABTZ-1-resistant strains were cross-resistant to known inhibitors of bacterial translation. ABTZ-1 represents a promising new class of antibacterial agents.
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, 600 S. Mathews Avenue, Urbana, IL 61801, USA.
authors.forename: Nora R
authors.initials: NR
authors.lastname: Eibergen
authors.forename: Isak
authors.initials: I
authors.lastname: Im
authors.forename: Nisha Y
authors.initials: NY
authors.lastname: Patel
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hergenrother
mesh_terms: D000900:Anti-Bacterial Agents / Q000096:biosynthesis / Q000737:chemistry / Q000494:pharmacology*; D052160:Benzothiazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016983:Enterococcus / Q000187:drug effects*; D006801:Humans; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011804:Quinolines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D020713:Vancomycin Resistance / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D052160:Benzothiazoles; D011804:Quinolines