Publications by authors named "Julia E A Mundy"

3 Publications

  • Page 1 of 1

The pentapeptide-repeat protein, MfpA, interacts with mycobacterial DNA gyrase as a DNA T-segment mimic.

Proc Natl Acad Sci U S A 2021 Mar;118(11)

Department of Biological Chemistry, John Innes Centre, NR4 7UH Norwich, United Kingdom;

DNA gyrase, a type II topoisomerase, introduces negative supercoils into DNA using ATP hydrolysis. The highly effective gyrase-targeted drugs, fluoroquinolones (FQs), interrupt gyrase by stabilizing a DNA-cleavage complex, a transient intermediate in the supercoiling cycle, leading to double-stranded DNA breaks. MfpA, a pentapeptide-repeat protein in mycobacteria, protects gyrase from FQs, but its molecular mechanism remains unknown. Here, we show that MfpA (MsMfpA) inhibits negative supercoiling by gyrase (Msgyrase) in the absence of FQs, while in their presence, MsMfpA decreases FQ-induced DNA cleavage, protecting the enzyme from these drugs. MsMfpA stimulates the ATPase activity of Msgyrase by directly interacting with the ATPase domain (MsGyrB47), which was confirmed through X-ray crystallography of the MsMfpA-MsGyrB47 complex, and mutational analysis, demonstrating that MsMfpA mimics a T (transported) DNA segment. These data reveal the molecular mechanism whereby MfpA modulates the activity of gyrase and may provide a general molecular basis for the action of other pentapeptide-repeat proteins.
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http://dx.doi.org/10.1073/pnas.2016705118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980463PMC
March 2021

Exploring the Chemical Space of Benzothiazole-Based DNA Gyrase B Inhibitors.

ACS Med Chem Lett 2020 Dec 15;11(12):2433-2440. Epub 2020 Oct 15.

University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.

We designed and synthesized a series of inhibitors of the bacterial enzymes DNA gyrase and DNA topoisomerase IV, based on our recently published benzothiazole-based inhibitor bearing an oxalyl moiety. To improve the antibacterial activity and retain potent enzymatic activity, we systematically explored the chemical space. Several strategies of modification were followed: varying substituents on the pyrrole carboxamide moiety, alteration of the central scaffold, including variation of substitution position and, most importantly, modification of the oxalyl moiety. Compounds with acidic, basic, and neutral properties were synthesized. To understand the mechanism of action and binding mode, we have obtained a crystal structure of compound , bearing a primary amino group, in complex with the N-terminal domain of gyrase B (24 kDa) (PDB: ). Compound , with a low molecular weight of 383 Da, potent inhibitory activity on gyrase (IC = 9.5 nM), potent antibacterial activity on (MIC = 3.13 μM), and efflux impaired strain (MIC = 0.78 μM), is an important contribution for the development of novel gyrase and topoisomerase IV inhibitors in Gram-negative bacteria.
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http://dx.doi.org/10.1021/acsmedchemlett.0c00416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734788PMC
December 2020

Biosynthesis of an Anti-Addiction Agent from the Iboga Plant.

J Am Chem Soc 2019 08 6;141(33):12979-12983. Epub 2019 Aug 6.

Department of Natural Product Biosynthesis , Max Planck Institute of Chemical Ecology , Hans-Knöll-Straße 8 , 07745 Jena , Germany.

(-)-Ibogaine and (-)-voacangine are plant derived psychoactives that show promise as treatments for opioid addiction. However, these compounds are produced by hard to source plants, making these chemicals difficult for broad-scale use. Here we report the complete biosynthesis of (-)-voacangine, and de-esterified voacangine, which is converted to (-)-ibogaine by heating, enabling biocatalytic production of these compounds. Notably, (-)-ibogaine and (-)-voacangine are of the opposite enantiomeric configuration compared to the other major alkaloids found in this natural product class. Therefore, this discovery provides insight into enantioselective enzymatic formal Diels-Alder reactions.
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http://dx.doi.org/10.1021/jacs.9b05999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6706869PMC
August 2019