Baulamycins A and B, Broad-Spectrum Antibiotics Identified as Inhibitors of Siderophore Biosynthesis in Staphylococcus aureus and Bacillus anthracis

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dc.creatorTripathi, Ashootosh
dc.creatorSchofield, Michael M.
dc.creatorChlipala, George E.
dc.creatorSchultz, Pamela J.
dc.creatorYim, Isaiah
dc.creatorNewmister, Sean A.
dc.creatorNusca, Tyler D.
dc.creatorScaglione, Jamie B.
dc.creatorHanna, Philip C.
dc.creatorTamayo Castillo, Giselle
dc.creatorSherman, David H.
dc.date.accessioned2023-01-03T13:44:56Z
dc.date.available2023-01-03T13:44:56Z
dc.date.issued2014
dc.descriptionSe incluye el artículo completo y una corrección del mismoes_ES
dc.description.abstractSiderophores 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 agentses_ES
dc.description.procedenceUCR::Vicerrectoría de Docencia::Ciencias Básicas::Facultad de Ciencias::Escuela de Químicaes_ES
dc.description.procedenceUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Básicas::Centro de Investigaciones en Productos Naturales (CIPRONA)es_ES
dc.description.sponsorshipUniversidad de Costa Ricaes_ES
dc.identifier.citationhttps://pubs.acs.org/doi/full/10.1021/ja4115924es_ES
dc.identifier.doi10.1021/ja4115924
dc.identifier.issn0002-7863
dc.identifier.issn1520-5126
dc.identifier.urihttps://hdl.handle.net/10669/87980
dc.language.isoenges_ES
dc.rightsacceso embargado
dc.sourceJournal of the American Chemical Society, 136(4), p. 1579-1586es_ES
dc.subjectAntimicrobial agentses_ES
dc.subjectBACTERIAes_ES
dc.subjectInhibitiones_ES
dc.subjectPeptideses_ES
dc.subjectPROTEINSes_ES
dc.subjectDRUGSes_ES
dc.titleBaulamycins A and B, Broad-Spectrum Antibiotics Identified as Inhibitors of Siderophore Biosynthesis in Staphylococcus aureus and Bacillus anthracises_ES
dc.typeartículo originales_ES

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