A multivalent approach to drug discovery for novel antibiotics.
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.
Long
Daniel D
DD
Theravance, Inc., San Francisco, CA 94080, USA. dlong@theravance.com
Aggen
James B
JB
Christensen
Burton G
BG
Judice
J Kevin
JK
Hegde
Sharath S
SS
Kaniga
Koné
K
Krause
Kevin M
KM
Linsell
Martin S
MS
Moran
Edmund J
EJ
Pace
John L
JL
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
D000900:Anti-Bacterial Agents; D006020:Glycopeptides; D047090:beta-Lactams