title: Exploring the positional attachment of glycopeptide/beta-lactam heterodimers.
abstract: Further investigations towards novel glycopeptide/beta-lactam heterodimers are reported. Employing a multivalent approach to drug discovery, vancomycin and cephalosporin synthons, 4, 2, 5 and 10, 18, 25 respectively, were chemically linked to yield heterodimer antibiotics. These novel compounds were designed to inhibit Gram-positive bacterial cell wall biosynthesis by simultaneously targeting the principal cellular targets of both glycopeptides and beta-lactams. The positional attachment of both the vancomycin and the cephalosporin central cores has been explored and the SAR is reported. This novel class of bifunctional antibiotics 28-36 all displayed remarkable potency against a wide range of Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA). A subset of compounds, 29, 31 and 35 demonstrated excellent bactericidal activity against MRSA (ATCC 33591) and 31 and 35 also exhibited superb in vivo efficacy in a mouse model of MRSA infection. As a result of this work compound 35 was selected as a clinical candidate, TD-1792.
authors.affiliation: Theravance, Inc., San Francisco, CA 94080, USA. dlong@theravance.com
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Long
authors.forename: James B
authors.initials: JB
authors.lastname: Aggen
authors.forename: Jason
authors.initials: J
authors.lastname: Chinn
authors.forename: Seok-Ki
authors.initials: SK
authors.lastname: Choi
authors.forename: Burton G
authors.initials: BG
authors.lastname: Christensen
authors.forename: Paul R
authors.initials: PR
authors.lastname: Fatheree
authors.forename: David
authors.initials: D
authors.lastname: Green
authors.forename: Sharath S
authors.initials: SS
authors.lastname: Hegde
authors.forename: J Kevin
authors.initials: JK
authors.lastname: Judice
authors.forename: Koné
authors.initials: K
authors.lastname: Kaniga
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Krause
authors.forename: Michael
authors.initials: M
authors.lastname: Leadbetter
authors.forename: Martin S
authors.initials: MS
authors.lastname: Linsell
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Marquess
authors.forename: Edmund J
authors.initials: EJ
authors.lastname: Moran
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Nodwell
authors.forename: John L
authors.initials: JL
authors.lastname: Pace
authors.forename: Sean G
authors.initials: SG
authors.lastname: Trapp
authors.forename: S Derek
authors.initials: SD
authors.lastname: Turner
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002511:Cephalosporins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D019281:Dimerization; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D005260:Female; D006020:Glycopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006094:Gram-Positive Bacteria / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D047090:beta-Lactams / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014640:Vancomycin
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D006020:Glycopeptides; D047090:beta-Lactams; C539430:cefilavancin; D014640:Vancomycin