TY - JOUR
T1 - Biological characterization of the hygrobafilomycin antibiotic JBIR-100 and bioinformatic insights into the hygrolide family of natural products
AU - Molloy, Evelyn M.
AU - Tietz, Jonathan I.
AU - Blair, Patricia M.
AU - Mitchell, Douglas A.
N1 - Funding Information:
This work was supported in part by a NIH Director’s New Innovator Award Program ( DP2 OD008463 to D.A.M.), the David and Lucile Packard Fellowship for Science and Engineering (to D.A.M.), the Robert C. and Carolyn J. Springborn Endowment (to J.I.T.). P.M.B. and J.I.T. were supported in part supported by ACS Division of Medicinal Chemistry predoctoral fellowships. The Bruker UltrafleXtreme MALDI-TOF/TOF mass spectrometer was purchased in part with a grant from the National Center for Research Resources, National Institutes of Health (S10 RR027109 A). We thank Parth Patel for contribution of bioinformatics code used for gene cluster analysis. We also thank Dr. Courtney L. Cox for helpful bioinformatics advice and Dr. Lingyang Zhu (Univ. Illinois NMR Laboratory) for assistance with collection of NMR spectra.
Publisher Copyright:
© 2016 Elsevier Ltd
PY - 2016
Y1 - 2016
N2 - The hygrolides, a family of 16-member-ring-containing plecomacrolides produced by Actinobacteria, exhibit numerous reported bioactivities. Using HR-MS/MS, nucleophilic 1,4-addition-based labeling, NMR, and bioinformatic analysis, we identified Streptomyces varsoviensis as a novel producer of JBIR-100, a fumarate-containing hygrolide, and elucidated the previously unknown stereochemistry of the natural product. We investigated the antimicrobial activity of JBIR-100, with preliminary insight into mode of action indicating that it perturbs the membrane of Bacillus subtilis. S. varsoviensis is known to produce compounds from multiple hygrolide sub-families, namely hygrobafilomycins (JBIR-100 and hygrobafilomycin) and bafilomycins (bafilomycin C1and D). In light of this, we identified the biosynthetic gene cluster for JBIR-100, which, to our knowledge, represents the first reported for a hygrobafilomycin. Finally, we performed a bioinformatic analysis of the hygrolide family, describing clusters from known and predicted producers. Our results indicate that potential remains for the Actinobacteria to yield novel hygrolide congeners, perhaps with differing biological activities.
AB - The hygrolides, a family of 16-member-ring-containing plecomacrolides produced by Actinobacteria, exhibit numerous reported bioactivities. Using HR-MS/MS, nucleophilic 1,4-addition-based labeling, NMR, and bioinformatic analysis, we identified Streptomyces varsoviensis as a novel producer of JBIR-100, a fumarate-containing hygrolide, and elucidated the previously unknown stereochemistry of the natural product. We investigated the antimicrobial activity of JBIR-100, with preliminary insight into mode of action indicating that it perturbs the membrane of Bacillus subtilis. S. varsoviensis is known to produce compounds from multiple hygrolide sub-families, namely hygrobafilomycins (JBIR-100 and hygrobafilomycin) and bafilomycins (bafilomycin C1and D). In light of this, we identified the biosynthetic gene cluster for JBIR-100, which, to our knowledge, represents the first reported for a hygrobafilomycin. Finally, we performed a bioinformatic analysis of the hygrolide family, describing clusters from known and predicted producers. Our results indicate that potential remains for the Actinobacteria to yield novel hygrolide congeners, perhaps with differing biological activities.
KW - Antifungal
KW - Antimicrobial
KW - Bioinformatics
KW - Hygrobafilomycin
KW - Hygrolide
KW - JBIR-100
KW - Nucleophilic 1,4-addition
KW - Plecomacrolide
KW - Polyketide
KW - Resistance mapping
KW - Streptomyces varsoviensis
KW - TS155-2
KW - Whole-genome sequencing
UR - http://www.scopus.com/inward/record.url?scp=84973890112&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84973890112&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2016.05.021
DO - 10.1016/j.bmc.2016.05.021
M3 - Article
C2 - 27234886
AN - SCOPUS:84973890112
SN - 0968-0896
VL - 24
SP - 6276
EP - 6290
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 24
ER -