title: Anthracimycin activity against contemporary methicillin-resistant Staphylococcus aureus.
abstract: Anthracimycin is a recently discovered novel marine-derived compound with activity against Bacillus anthracis. We tested anthracimycin against an expanded panel of Staphylococcus aureus strains in vitro and in vivo. All strains of S. aureus tested, including methicillin-susceptible, methicillin-resistant (MRSA) and vancomycin-resistant strains of S. aureus, were susceptible to anthracimycin at MIC values of ⩽0.25 mg l(-1). Although its postantibiotic effects were minimal, anthracimycin exhibited potent and rapid bactericidal activity, with a >4-log kill of USA300 MRSA within 3 h at five times its MIC. At concentrations significantly below the MIC, anthracimycin slowed MRSA growth and potentiated the bactericidal activity of the human cathelicidin, LL-37. The bactericidal activity of anthracimycin was somewhat mitigated in the presence of 20% human serum, and the compound was minimally toxic to human cells, with an IC50 (inhibitory concentration 50)=70 mg l(-1) against human carcinoma cells. At concentrations near the MIC, anthracimycin inhibited S. aureus nucleic acid synthesis as determined by optimized macromolecular synthesis methodology, with inhibition of DNA and RNA synthesis occurring in the absence of DNA intercalation. Anthracimycin at a single dose of 1 or 10 mg kg(-1) was able to protect mice from MRSA-induced mortality in a murine peritonitis model of infection. Anthracimycin provides an interesting new scaffold for future development of a novel MRSA antibiotic.
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Hensler
authors.affiliation: Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA, USA.
authors.forename: Kyoung Hwa
authors.initials: KH
authors.lastname: Jang
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
authors.forename: Wdee
authors.initials: W
authors.lastname: Thienphrapa
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Vuong
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
authors.forename: Dan N
authors.initials: DN
authors.lastname: Tran
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
authors.forename: Evaristus
authors.initials: E
authors.lastname: Soubih
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
authors.forename: Leo
authors.initials: L
authors.lastname: Lin
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA.
authors.forename: Nina M
authors.initials: NM
authors.lastname: Haste
authors.affiliation: Trius Therapeutics, San Diego, CA, USA.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Cunningham
authors.affiliation: Trius Therapeutics, San Diego, CA, USA.
authors.forename: Bryan P
authors.initials: BP
authors.lastname: Kwan
authors.affiliation: Trius Therapeutics, San Diego, CA, USA.
authors.forename: Karen Joy
authors.initials: KJ
authors.lastname: Shaw
authors.affiliation: Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA, USA.
authors.forename: William
authors.initials: W
authors.lastname: Fenical
authors.affiliation: 1] Department of Pediatrics, University of California San Diego, La Jolla, CA, USA [2] Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D008712:Methicillin / Q000494:pharmacology; D016106:Methicillin Resistance; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D010538:Peritonitis / Q000188:drug therapy / Q000382:microbiology*; D061065:Polyketides / Q000009:adverse effects / Q000494:pharmacology*; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D014640:Vancomycin / Q000494:pharmacology; D020713:Vancomycin Resistance
chemical_list: D000900:Anti-Bacterial Agents; D061065:Polyketides; C583934:anthracimycin; D014640:Vancomycin; D008712:Methicillin
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