title: Burkholdines from Burkholderia ambifaria: antifungal agents and possible virulence factors.
abstract: Burkholdines are cyclic lipopeptides with unusual antifungal potency, making them promising leads as a new class of antifungal agents. However, a recent report using knockout mutagenesis indicates that these and related compounds, such as occidiofungins, xylocandins, and cepacidines, may also be synonymous with the long-known hemolytic virulence factors found in diverse Burkholderia isolates. Because of their possible roles in causing Burkholderia infections or curing fungal infections, it is important to fully define their structures and biological activities using pure compounds. Here, we report the structures of three further burkholdines, Bk-1119, Bk-1213, and Bk-1215, which were elucidated using spectroscopic methods. The absolute configuration of this compound class was determined for the first time using a combination of spectroscopy and chemical degradation techniques. Antifungal and hemolytic activities were assessed for five pure burkholdines, representative of the structural diversity of this lipopeptide class. All of the burkholdines were potent antifungal and hemolytic agents, validating their probable role in virulence. However, one of the burkholdines (Bk-1119) exhibited a >30-fold selectivity for fungi versus sheep erythrocytes and was more than 25-fold more potent than amphotericin against some fungal strains. Therefore, burkholdines have potential to selectively target fungal infections.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Utah, Salt Lake City, Utah 84112, USA.
authors.forename: Zhenjian
authors.initials: Z
authors.lastname: Lin
authors.forename: Joseph O
authors.initials: JO
authors.lastname: Falkinham
authors.forename: Kamilia A
authors.initials: KA
authors.lastname: Tawfik
authors.forename: Peter
authors.initials: P
authors.lastname: Jeffs
authors.forename: Brian
authors.initials: B
authors.lastname: Bray
authors.forename: George
authors.initials: G
authors.lastname: Dubay
authors.forename: James E
authors.initials: JE
authors.lastname: Cox
authors.forename: Eric W
authors.initials: EW
authors.lastname: Schmidt
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D019117:Burkholderia / Q000737:chemistry*; D055666:Lipopeptides / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D037521:Virulence Factors / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; C576969:Bk-1119; C576968:Bk-1213; C576970:Bk-1215; D055666:Lipopeptides; D010456:Peptides, Cyclic; D037521:Virulence Factors