title: A multivalent approach to drug discovery for novel antibiotics.
abstract: The design, synthesis and antibacterial activity of novel glycopeptide/beta-lactam heterodimers is reported. Employing a multivalent approach to drug discovery, vancomycin and cephalosporin synthons, A and B 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 antibiotics 8a-f displayed remarkable potency against a wide range of Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA). Compound 8e demonstrated excellent bactericidal activity against MRSA (ATCC 33591) and initial evidence supports a multivalent mechanism of action for this important new class of antibiotic.
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: Burton G
authors.initials: BG
authors.lastname: Christensen
authors.forename: J Kevin
authors.initials: JK
authors.lastname: Judice
authors.forename: Sharath S
authors.initials: SS
authors.lastname: Hegde
authors.forename: Koné
authors.initials: K
authors.lastname: Kaniga
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Krause
authors.forename: Martin S
authors.initials: MS
authors.lastname: Linsell
authors.forename: Edmund J
authors.initials: EJ
authors.lastname: Moran
authors.forename: John L
authors.initials: JL
authors.lastname: Pace
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D002473:Cell Wall / Q000187:drug effects; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D006020:Glycopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006094:Gram-Positive Bacteria / Q000187:drug effects; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D047090:beta-Lactams / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D006020:Glycopeptides; D047090:beta-Lactams