title: Broad-spectrum antibiotic activity of the arylomycin natural products is masked by natural target mutations.
abstract: Novel classes of broad-spectrum antibiotics are needed to treat multidrug-resistant pathogens. The arylomycin class of natural products inhibits a promising antimicrobial target, type I signal peptidase (SPase), but upon initial characterization appeared to lack whole-cell activity against most pathogens. Here, we show that Staphylococcus epidermidis, which is sensitive to the arylomycins, evolves resistance via mutations in SPase and that analogous mutations are responsible for the natural resistance of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. We identify diverse bacteria lacking these mutations and demonstrate that most are sensitive to the arylomycins. The results illustrate that the arylomycins have a broad-spectrum of activity and are viable candidates for development into therapeutics. The results also raise the possibility that naturally occurring resistance may have masked other natural product scaffolds that might be developed into therapeutics.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Smith
authors.forename: Tucker C
authors.initials: TC
authors.lastname: Roberts
authors.forename: Floyd E
authors.initials: FE
authors.lastname: Romesberg
mesh_terms: D019943:Amino Acid Substitution; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D024881:Drug Resistance, Bacterial / Q000235:genetics; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D013212:Staphylococcus epidermidis / Q000201:enzymology
chemical_list: D000900:Anti-Bacterial Agents; D008565:Membrane Proteins; D009842:Oligopeptides; C488532:arylomycin A2; D012697:Serine Endopeptidases; C026515:type I signal peptidase