title: Baulamycins A and B, broad-spectrum antibiotics identified as inhibitors of siderophore biosynthesis in Staphylococcus aureus and Bacillus anthracis.
abstract: Siderophores are high-affinity iron chelators produced by microorganisms and frequently contribute to the virulence of human pathogens. Targeted inhibition of the biosynthesis of siderophores staphyloferrin B of Staphylococcus aureus and petrobactin of Bacillus anthracis hold considerable potential as a single or combined treatment for methicillin-resistant S. aureus (MRSA) and anthrax infection, respectively. The biosynthetic pathways for both siderophores involve a nonribosomal peptide synthetase independent siderophore (NIS) synthetase, including SbnE in staphyloferrin B and AsbA in petrobactin. In this study, we developed a biochemical assay specific for NIS synthetases to screen for inhibitors of SbnE and AsbA against a library of marine microbial-derived natural product extracts (NPEs). Analysis of the NPE derived from Streptomyces tempisquensis led to the isolation of the novel antibiotics baulamycins A (BmcA, 6) and B (BmcB, 7). BmcA and BmcB displayed in vitro activity with IC50 values of 4.8 μM and 19 μM against SbnE and 180 μM and 200 μM against AsbA, respectively. Kinetic analysis showed that the compounds function as reversible competitive enzyme inhibitors. Liquid culture studies with S. aureus , B. anthracis , E. coli , and several other bacterial pathogens demonstrated the capacity of these natural products to penetrate bacterial barriers and inhibit growth of both Gram-positive and Gram-negative species. These studies provide proof-of-concept that natural product inhibitors targeting siderophore virulence factors can provide access to novel broad-spectrum antibiotics, which may serve as important leads for the development of potent anti-infective agents.
authors.affiliation: Life Sciences Institute, University of Michigan , 210 Washtenaw Avenue, Ann Arbor, Michigan 48109, United States.
authors.forename: Ashootosh
authors.initials: A
authors.lastname: Tripathi
authors.forename: Michael M
authors.initials: MM
authors.lastname: Schofield
authors.forename: George E
authors.initials: GE
authors.lastname: Chlipala
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Schultz
authors.forename: Isaiah
authors.initials: I
authors.lastname: Yim
authors.forename: Sean A
authors.initials: SA
authors.lastname: Newmister
authors.forename: Tyler D
authors.initials: TD
authors.lastname: Nusca
authors.forename: Jamie B
authors.initials: JB
authors.lastname: Scaglione
authors.forename: Philip C
authors.initials: PC
authors.lastname: Hanna
authors.forename: Giselle
authors.initials: G
authors.lastname: Tamayo-Castillo
authors.forename: David H
authors.initials: DH
authors.lastname: Sherman
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001408:Bacillus anthracis / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D001688:Biological Products / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000187:drug effects*; D057166:High-Throughput Screening Assays; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D017262:Siderophores / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D013211:Staphylococcus aureus / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001688:Biological Products; D017262:Siderophores; C015018:baumycins; D003630:Daunorubicin