title: Novel bacterial metabolite merochlorin A demonstrates in vitro activity against multi-drug resistant methicillin-resistant Staphylococcus aureus.
abstract: BACKGROUND
  We evaluated the in vitro activity of a merochlorin A, a novel compound with a unique carbon skeleton, against a spectrum of clinically relevant bacterial pathogens and against previously characterized clinical and laboratory Staphylococcus aureus isolates with resistance to numerous antibiotics.
  
  
  METHODS
  Merochlorin A was isolated and purified from a marine-derived actinomycete strain CNH189. Susceptibility testing for merochlorin A was performed against previously characterized human pathogens using broth microdilution and agar dilution methods. Cytotoxicity was assayed in tissue culture assays at 24 and 72 hours against human HeLa and mouse sarcoma L929 cell lines.
  
  
  RESULTS
  The structure of as new antibiotic, merochlorin A, was assigned by comprehensive spectroscopic analysis. Merochlorin A demonstrated in vitro activity against Gram-positive bacteria, including Clostridium dificile, but not against Gram negative bacteria. In S. aureus, susceptibility was not affected by ribosomal mutations conferring linezolid resistance, mutations in dlt or mprF conferring resistance to daptomycin, accessory gene regulator knockout mutations, or the development of the vancomycin-intermediate resistant phenotype. Merochlorin A demonstrated rapid bactericidal activity against MRSA. Activity was lost in the presence of 20% serum.
  
  
  CONCLUSIONS
  The unique meroterpenoid, merochlorin A demonstrated excellent in vitro activity against S. aureus and C. dificile and did not show cross-resistance to contemporary antibiotics against Gram positive organisms. The activity was, however, markedly reduced in 20% human serum. Future directions for this compound may include evaluation for topical use, coating biomedical devices, or the pursuit of chemically modified derivatives of this compound that retain activity in the presence of serum.
authors.affiliation: Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, California, United States of America. gsakoulas@ucsd.edu
authors.forename: George
authors.initials: G
authors.lastname: Sakoulas
authors.forename: Sang-Jip
authors.initials: SJ
authors.lastname: Nam
authors.forename: Sandra
authors.initials: S
authors.lastname: Loesgen
authors.forename: William
authors.initials: W
authors.lastname: Fenical
authors.forename: Paul R
authors.initials: PR
authors.lastname: Jensen
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
authors.forename: Mary
authors.initials: M
authors.lastname: Hensler
mesh_terms: D039903:Actinobacteria / Q000378:metabolism*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D059001:Aquatic Organisms / Q000378:metabolism; D001567:Benzocycloheptenes / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects*; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D054830:Sesterterpenes / Q000737:chemistry / Q000494:pharmacology*; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology
chemical_list: D000900:Anti-Bacterial Agents; D001567:Benzocycloheptenes; D054830:Sesterterpenes; C573231:merochlorin A