title: Natural lipopeptide antibiotic tripropeptin C revitalizes and synergistically potentiates the activity of beta-lactams against methicillin-resistant Staphylococcus aureus.
abstract: Tripropeptin C (TPPC) is a natural calcium-ion-dependent lipopeptide antibiotic that inhibits peptidoglycan biosynthesis by binding to prenyl pyrophosphate. It displays very potent antimicrobial activity both in vitro and in a mouse model of methicillin-resistant Staphylococcus aureus (MRSA) septicemia. The combination of TPPC with all classes of beta-lactams tested (including penam, carbapenem, cephem and oxacephem) showed highly synergistic (SYN) effects against MRSA strains, but not against methicillin-sensitive S. aureus strains. These SYN effects were observed with both a checkerboard methodology and a time-kill analysis. The TPPC analog, bis-methyl ester-TPPC, which has neither antimicrobial activity nor the ability to bind prenyl pyrophosphate, also potentiated the activity of beta-lactams. This result indicates that the mechanism of the SYN activity of TPPC is independent of its binding to prenyl pyrophosphate. Therefore, synergistically enhancing the anti-MRSA activities of TPPC and beta-lactams by combining them is a novel and potentially powerful therapeutic strategy for MRSA infections.
authors.affiliation: Laboratory of Disease Biology, Institute of Microbial Chemistry (BIKAKEN), Shinagawa, Tokyo, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Hashizume
authors.affiliation: Institute of Microbial Chemistry (BIKAKEN) Hiyoshi, Kawasaki, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Laboratory of Disease Biology, Institute of Microbial Chemistry (BIKAKEN), Shinagawa, Tokyo, Japan.
authors.forename: Shigeko
authors.initials: S
authors.lastname: Harada
authors.affiliation: Laboratory of Disease Biology, Institute of Microbial Chemistry (BIKAKEN), Shinagawa, Tokyo, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Nomoto
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017576:Daptomycin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011756:Diphosphates / Q000378:metabolism; D004336:Drug Antagonism; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects; D004357:Drug Synergism; D007700:Kinetics; D055666:Lipopeptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D016106:Methicillin Resistance / Q000187:drug effects; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development; D008745:Methylation; D008826:Microbial Sensitivity Tests; D010456:Peptides, Cyclic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D054876:Prenylation; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development; D047090:beta-Lactams / Q000819:agonists* / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D011756:Diphosphates; D055666:Lipopeptides; D010456:Peptides, Cyclic; D047090:beta-Lactams; C000601004:tripropeptin C; D017576:Daptomycin