Targeting an Essential GTPase Obg for the Development of Broad-Spectrum Antibiotics Public Deposited

http://ir.library.oregonstate.edu/concern/articles/vm40xt36h

Supporting information is available online at:  http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0148222

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  • A promising new drug target for the development of novel broad-spectrum antibiotics is the highly conserved small GTPase Obg (YhbZ, CgtA), a protein essential for the survival of all bacteria including Neisseria gonorrhoeae (GC). GC is the agent of gonorrhea, a prevalent sexually transmitted disease resulting in serious consequences on reproductive and neonatal health. A preventive anti-gonorrhea vaccine does not exist, and options for effective antibiotic treatments are increasingly limited. To address the dire need for alternative antimicrobial strategies, we have designed and optimized a 384-well GTPase assay to identify inhibitors of Obg using as a model Obg protein from GC, Obg[subscript]GC. The assay was validated with a pilot screen of 40,000 compounds and achieved an average Z’ value of 0.58 ± 0.02, which suggests a robust assay amenable to high-throughput screening. We developed secondary assessments for identified lead compounds that utilize the interaction between Obg[subscript]GC and fluorescent guanine nucleotide analogs, mant-GTP and mant-GDP, and an Obg[subscript]GC variant with multiple alterations in the G-domains that prevent nucleotide binding. To evaluate the broad-spectrum potential of Obg[subscript]GC inhibitors, Obg proteins of Klebsiella pneumoniae and methicillin-resistant Staphylococcus aureus were assessed using the colorimetric and fluorescence-based activity assays. These approaches can be useful in identifying broad-spectrum Obg inhibitors and advancing the therapeutic battle against multidrug resistant bacteria
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  • Bonventre, J. A., Zielke, R. A., Korotkov, K. V., & Sikora, A. E. (2016). Targeting an Essential GTPase Obg for the Development of Broad-Spectrum Antibiotics. PLoS ONE, 11(2), e0148222. doi:10.1371/journal.pone.0148222
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  • description.provenance : Approved for entry into archive by Patricia Black(patricia.black@oregonstate.edu) on 2016-03-11T15:42:46Z (GMT) No. of bitstreams: 2 license_rdf: 1370 bytes, checksum: cd1af5ab51bcc7a5280cf305303530e9 (MD5) BonventreTargetingEssentialGTPaseObg.PDF: 658732 bytes, checksum: 156447007ddbf469e70d230a5478cfc1 (MD5)
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