dna gyrase is inhibited by tetracyclines

Ther. bioRxiv. The inset shows the loop within the GyrB ATPase domain that is specific to Corynebacteriales gyrases and how this loop occludes the evybactin binding site in the ATPase open conformation of the enzyme. Other data that support the findings of this study are available from the corresponding author upon reasonable request. Epub 2021 Apr 1. Rev. 2022 Jan 6;23(2):619. doi: 10.3390/ijms23020619. Which of the following statements on replication in E.coli is correct? Nat Commun 12, 150 (2021). USA 74, 47724776 (1977). Discovery of anti-TB agents that target the cell-division protein FtsZ. PubMedGoogle Scholar, Department of Biochemistry and Molecular Biology, East Tennessee State University, Johnson, Tennessee, Fisher, L.M., Pan, XS. Internet Explorer). f, 1H-13C HMBC. This work was supported by National Institutes of Health grants P01AI118687 (K.L. Biol. The crystal structures used from the pdb database search are publicly available in Protein Data Bank repository (PDB IDs: 2XCS, 5CDP, 1GJD, 1UHI, 4CMJ, 4JYI, 5A86, 5YC6, 5YC7). performed design, chemical reactions, and biological experiments. Nucleic Acids Res. D Struct. It is essential in all bacteria but absent from higher eukaryotes, making it an attractive target for antibacterials. Google Scholar. Google Scholar. Bhowmick J, Nag M, Ghosh P, Rajmani RS, Chatterjee R, Karmakar K, Chandra K, Chatterjee J, Chakravortty D, Varadarajan R. EMBO Rep. 2023 Jul 5;24(7):e55338. Odilorhabdins, antibacterial agents that cause miscoding by binding at a new ribosomal site. CAS 95: DNA Nonejuie, P., Burkart, M., Pogliano, K. & Pogliano, J. Bacterial cytological profiling rapidly identifies the cellular pathways targeted by antibacterial molecules. Evybactin is a DNA gyrase inhibitor that selectively kills Mycobacterium tuberculosis. Bioorg Chem. Natl Acad. In vitro and in vivo characterization of NOSO-502, a novel inhibitor of bacterial translation. The two compounds inhibited DNA gyrase ATPase activity with IC50 values of 2.69 and 2.46 M, respectively, suggesting this to be the likely basis of their antitubercular activity. 8 Evybactin and moxifloxacin stimulated cleavage activity of, Extended Data Fig. Bookshelf Luna, B. et al. Biol. Acta Crystallogr. 17, 64406450 (2015). Durcik, M. et al. Future Med Chem 10:12071227. 29, 171180 (2019). 54, 240 (2015). Widespread resistance to clinically important antibiotics such as beta-lactams and macrolides has stimulated the development of novel gyrase and topo IV inhibitors especially against Streptococcus pneumoniae and other Gram-positive pathogens. 3, 249282. Phys. Braun, V., Pramanik, A., Gwinner, T., Koberle, M. & Bohn, E. Sideromycins: tools and antibiotics. World Health Organization. Biol. Pan, X.-S., Yague, G., and Fisher, L. M. (2001) Quinolone resistance mutations in Streptococcus pneumoniae GyrA and ParC proteins: Mechanistic insights into quinolone action from enzymatic analysis, intracellular levels, and phenotypes of wild-type and mutant proteins. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Extended Data Fig. Novak, M., Foroutan-Nejad, C. & Marek, R. Asymmetric bifurcated halogen bonds. Acta Crystallogr. DNA Gyrase Inhibitors. Correct Answer nalidixic acid DNA Replication problems Search Results 1. Nature 576, 459464 (2019). We acknowledge the Korea Basic Science Institute for providing NMR data. Extended Data Fig. Clark, T. -Holes. Exploring Alternative Pathways to Target Bacterial Type II Topoisomerases Using NBTI Antibacterials: Beyond Halogen-Bonding Interactions. DNA gyrase is an A2B2 heterotetramer, comprised of two subunits, that is, A (encoded by gyrA, 97 KDa in E-coli) and B (encoded by gyrB, 90 KDa in E-coli ). Learn more. doi: 10.15252/embr.202255338. 2018 Sep;112:83-88. doi: 10.1016/j.tube.2018.08.005. 8600 Rockville Pike This proteinDNAinhibitor complex was incubated for 60min at room temperature and then centrifuged at 13,000g in a benchtop centrifuge for 30s prior to setting up the crystallization. Mol. By submitting a comment you agree to abide by our Terms and Community Guidelines. 2020 Aug 1;199:112326. doi: 10.1016/j.ejmech.2020.112326. PubMed Abo-Elghiet F, Rushdi A, Ibrahim MH, Mahmoud SH, Rabeh MA, Alshehri SA, El Menofy NG. Inhibiting ATP binding by DNA gyrase and topo IV with novobiocin enhanced the effect of low pH on DNA relaxation. CAS Nucleic Acids Res. 1 NMR structural determination of evybactin in DMSO-. Nat. PubMed To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. CAS Vanden Broeck, A., Lotz, C., Ortiz, J. What inhibitor of nucleic acid function disrupts . Characterisation of the DNA gyrase from the thermophilic - PubMed Google Scholar. Microbiol. Bacterial DNA gyrase is a type II topoisomerase that can introduce negative supercoils to DNA substrates and is a clinically-relevant target for the development of new antibacterials. Unauthorized use of these marks is strictly prohibited. 25, 247260 (2006). Determination of bacterial resistance to antibiotics of all classes (phenotypes) and mutations that are responsible for bacterial resistance to antibiotics (genetic analysis) are helpful. Future Med Chem. Provided by the Springer Nature SharedIt content-sharing initiative. Biochem. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). DNA gyrase has the ability to introduce a double-stranded break in DNA and it is thought to have an important role in . Thirty compounds were identified and selected as hits for in vitro biological assays, of which two compounds, G24 and G26, inhibited the growth of M. tuberculosis H37Rv with a minimal inhibitory concentration of 12.5 g/mL. sharing sensitive information, make sure youre on a federal & Boeckler, F. Principles and applications of halogen bonding in medicinal chemistry and chemical biology. Mycobacterium tuberculosis DNA gyrase manipulates the DNA topology using controlled breakage and religation of DNA driven by ATP hydrolysis. Thank you for visiting nature.com. Epub 2015 Mar 24. M. tuberculosis. In: Champney, W.S. Nature 466, 935951 (2010). Sacchettini, J. C., Rubin, E. J. The authors declare no competing interests. Article These approaches provide mechanistic insight on inhibitor action and allow identification of dual gyrase/topo IV targeting agents that can minimize the emergence of bacterial resistance. 7 Mutations at the evybactin binding site effect evybactin and moxifloxacin induced cleavage. & Osheroff, N. Human topoisomerase IIalpha uses a two-metal-ion mechanism for DNA cleavage. Bax, B. D. et al. Copyright Bentham Science Publishers; For any queries, please email at epub@benthamscience.net. PMC How antibiotics kill bacteria: from targets to networks All assays repeated at least 3 times with similar results. (PDF) DNA Gyrase as a Target for Quinolones - ResearchGate Google Scholar, Collin F, Karkare S, Maxwell A (2011) Exploiting bacterial DNA gyrase as a drug target: current state and perspectives. J. Infect. Provided by the Springer Nature SharedIt content-sharing initiative, Nature Chemical Biology (Nat Chem Biol) Bioisosteric Design Identifies Inhibitors of. Thiophene antibacterials that allosterically stabilize DNA-cleavage complexes with DNA gyrase. ADS TLS group definitions obtained from the TLSMD server (http://skuld.bmsc.washington.edu/~tlsmd/)56 were used in the later stages of refinement. Cleavage was conducted with 20 nM wild-type MtbGyrase or MtbGyrase GyrA mutants and 6 nM DNA. Theor. Crystallogr. https://doi.org/10.1038/s41589-022-01102-7, DOI: https://doi.org/10.1038/s41589-022-01102-7. CAS Chem. Xpert MTB/XDR for detection of pulmonary tuberculosis and resistance to isoniazid, fluoroquinolones, ethionamide, and amikacin. Domenech, P., Kobayashi, H., LeVier, K., Walker, G. C. & Barry, C. E. III BacA, an ABC transporter involved in maintenance of chronic murine infections with Mycobacterium tuberculosis. Rev. (1976) DNA gyrase:An enzyme that introduces superhelical turns into DNA. Google Scholar. CLSI. The source data of Fig. Novel tricyclics (e.g., GSK945237) as potent inhibitors of bacterial type IIA topoisomerases. official website and that any information you provide is encrypted 5, 570581 (2019). Acta Crystallogr. The financial support of this work from the Slovenian Research Agency (Grants P1-0017 and P1-0208) is gratefully acknowledged. It has three domains like GyrB, GyrA, and C-terminal domain. 594, 38983907 (2020). USA 113, 17061713 (2016). CAS If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate. Comput. X.-S. Pan and this work were supported by Project Grant BBD01882X1 from the Biotechnology and Biological Sciences Council of the United Kingdom. 2, 13051323 (2010). A. et al. Overexpression and Purification of Bacterial DNA Gyrase Unable to load your collection due to an error, Unable to load your delegates due to an error. CCP4i2: the new graphical user interface to the CCP4 program suite. Chem. Tari LW, Li X, Trzoss M, Bensen DC, Chen Z, Lam T, Zhang J, Lee SJ, Hough G, Phillipson D, Akers-Rodriguez S, Cunningham ML, Kwan BP, Nelson KJ, Castellano A, Locke JB, Brown-Driver V, Murphy TM, Ong VS, Pillar CM, Shinabarger DL, Nix J, Lightstone FC, Wong SE, Nguyen TB, Shaw KJ, Finn J. PLoS One. USA. HCl 50mM, glycerol 10% (v/v), EDTA 1mM, DTT 1mM) plus protease inhibitors (Roche Complete, EDTA-free tablets) and lysed in an Avestin cell disruptor. Nat. 2023 May 19;28(10):4184. doi: 10.3390/molecules28104184. Chem. The emerging bacterial resistance makes several existing antibiotic therapies ineffective. Dalhoff, A., Petersen, U. N.M., M.A., and A.M. supervised the research. Sci. PubMed J. Mol. Baranokov M, Kikelj D, Ila J (2018) Recent progress in the discovery and development of DNA gyrase B inhibitors. 62, 439450 (2006). PubMed J. Bacteriol. Thus, compounds G24 and G26 provide attractive starting templates for the optimization of antitubercular agents that act by targeting DNA gyrase. ez, J. Agents Chemother. 4, values are plotted as mean values SD, n=3 independent biochemical experiments. PubMed CAS A total of 3600 images with oscillation of 0.1 were recorded to a maximum resolution of 2.3. Thus, it . Gellert, M., Mizuuchi, K., Odea, M. H., Itoh, T. & Tomizawa, J. I. Nalidixic acid resistance: a second genetic character involved in DNA gyrase activity. 84, 33473354 (2012). Potent DNA gyrase inhibitors bind asymmetrically to their - Nature Prospects for developing new antibacterials targeting bacterial type IIA topoisomerases. Chem. 2018 Jul;103:923-938. doi: 10.1016/j.biopha.2018.04.021. How antibiotics kill bacteria: from targets to networks - PMC A. et al. the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in https://doi.org/10.1039/c9md00120d, World Health Organization (2018) WHO report on surveillance of antibiotic consumption: 20162018 early implementation, Department of Pharmaceutical Chemistry and QA, SVKMs Dr. Bhanuben Nanavati College of Pharmacy, Mumbai, India, Department of Pharmaceutical Chemistry, SVKMs Dr. Bhanuben Nanavati College of Pharmacy, Mumbai, India, You can also search for this author in D 60, 21262132 (2004). Ed. Cryst. Halogen bonding of (iodoethynyl)benzene derivatives in solution. Fluoroquinolones are commonly used effective antibacterial agents that target DNA gyrase, however the spectrum of side-effects and emerging bacterial resistance with no new drugs in the antibacterial pipeline has fuelled intensive research in this area. 2023 Mar 14:2023.03.14.532001. doi: 10.1101/2023.03.14.532001. 8600 Rockville Pike McNicholas, S., Potterton, E., Wilson, K. S. & Noble, M. E. Presenting your structures: the CCP4mg molecular-graphics software. The enzyme from Escherichia coli consists of two proteins, A and B (termed GyrA and GyrB), of molecular masses 97 and 90 kDa, respectively; the active enzyme is an A 2 B 2 complex.
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