Identification of novel bacterial DNA gyrase inhibitors: An in silico study

Hamzeh Rahimi, Ali Najafi, Habib Eslami, Babak Negahdari, Mehrdad Moosazadeh Moghaddam


Owing to essential role in bacterial survival, DNA gyrase has been exploited as a validated drug target. However, rapidly emerging resistance to gyrase-targeted drugs such as widely utilized fluoroquinolones reveals the necessity to develop novel compounds with new mechanism of actions against this enzyme. Here, an attempt has been made to identify new drug-like molecules for Shigella flexneri DNA gyrase inhibition through in silico approaches. The structural similarity search was carried out using the natural product simocyclinone D8, a unique gyrase inhibitor, to virtually screen ZINC database. A total of 11830 retrieved hits were further screened for selection of high-affinity compounds by implementing molecular docking followed by investigation of druggability according to Lipinski's rule, biological activity and physiochemical properties. Among the hits initially identified, three molecules were then confirmed to have reasonable gyrase-binding affinity and to follow Lipinski's rule. Based on these in silico findings, three compounds with different chemical structures from previously identified gyrase inhibitors were proposed as potential candidates for the treatment of fluoroquinolone-resistant strains and deserve further investigations.

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Collin F, Karkare S, Maxwell A. Exploiting bacterial DNA gyrase as a drug target: current state and perspectives. Appl Microbiol Biotechnol. 2011;92:479–497.

Alt S, Mitchenall LA, Maxwell A, Heide L. Inhibition of DNA gyrase and DNA topoisomerase IV of Staphylococcus aureus and Escherichia coli by aminocoumarin antibiotics. J Antimicrob Chemother. 2011;66:2061–2069.

Sissi C, Vazquez E, Chemello A, Mitchenall LA, Maxwell A, Palumbo M. Mapping simocyclinone D8 interaction with DNA gyrase: evidence for a new binding site on GyrB. Antimicrob Agents Chemother. 2010;54:213–220.

Flatman RH, Howells AJ, Heide L, Fiedler HP, Maxwell A. Simocyclinone D8, an inhibitor of DNA gyrase with a novel mode of action. Antimicrob Agents Chemother. 2005;49:1093–1100.

Edwards MJ, Flatman RH, Mitchenall LA, Stevenson CE, Maxwell A, Lawson DM. Crystallization and preliminary X-ray analysis of a complex formed between the antibiotic simocyclinone D8 and the DNA breakage-reunion domain of Escherichia coli DNA gyrase. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2009;65:846–848.

Hearnshaw SJ, Edwards MJ, Stevenson CE, Lawson DM, Maxwell A. A new crystal structure of the bifunctional antibiotic simocyclinone D8 bound to DNA gyrase gives fresh insight into the mechanism of inhibition. J Mol Biol. 2014;426:2023–2033.

Lindorff-Larsen K, Piana S, Palmo K, Maragakis P, Klepeis JL, Dror RO, et al. Improved side-chain torsion potentials for the Amber ff99SB protein force field. Proteins. 2010;78:1950–1958.

Van Der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJC. GROMACS: Fast, flexible, and free. J Comput Chem. 2005;26:1701–1718.

Trott O, Olson AJ. AutoDock Vina. Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 2010;31:455–461.

Laskowski RA, Swindells MB. LigPlot+: Multiple ligand-protein interaction diagrams for drug discovery. J Chem Inf Model. 2011;51:2778–2786.

Backman TWH, Cao Y, Girke T. ChemMine tools: An online service for analyzing and clustering small molecules. Nucleic Acids Res. 2011;39:1–6.

Cao Y, Charisi A, Cheng LC, Jiang T, Girke T. ChemmineR: A compound mining framework for R. Bioinformatics. 2008;24:1733–1734.

Cao Y, Jiang T, Girke T. A maximum common substructure-based algorithm for searching and predicting drug-like compounds. Bioinformatics. 2008;24:i366–i374.

Chen X, Reynolds CH. Performance of similarity measures in 2D fragment-based similarity searching: Comparison of structural descriptors and similarity coefficients. J Chem Inf Comput Sci. 2002;42:1407–1414.

Pu XY, Zhang Q, Pan JC, Shen Z, Zhang W. Spontaneous mutation frequency and molecular mechanisms of S. flexneri fluoroquinolone resistance under antibiotic selective stress. World J Microbiol Biotechnol. 2013;29:365–371.

Kim J, Jeon S, Kim H, Park M, Kim S, Kim S. Multiplex real-time polymerase chain reaction-based method for the rapid detection of GyrA and parC mutations in quinolone-resistant Escherichia coli and Shigella spp. Osong Public Heal Res Perspect. 2012;3:113–117.

Pu XY, Pan JC, Wang HQ, Zhang W, Huang ZC, Gu YM. Characterization of fluoroquinolone-resistant Shigella flexneri in Hangzhou area of China. J Antimicrob Chemother. 2009;63:917–920.

Kim JY, Kim SH, Jeon SM, Park MS, Rhie HG, Lee BK. Resistance to fluoroquinolones by the combination of target site mutations and enhanced expression of genes for efflux pumps in Shigella flexneri and Shigella sonnei strains isolated in Korea. Clin Microbiol Infect. 2008;14:760–765.

Madurga S, Sánchez-Céspedes J, Belda I, Vila J, Giralt E. Mechanism of binding of fluoroquinolones to the quinolone resistance-determining region of DNA gyrase: Towards an understanding of the molecular basis of quinolone resistance. Chembiochem. 2008;9:2081–2086.

Sadiq AA, Patel MR, Jacobson BA, Escobedo M, Ellis K, Oppegard LM, et al. Anti-proliferative effects of simocyclinone D8 (SD8), a novel catalytic inhibitor of topoisomerase II. Invest New Drugs. 2010;28:20–25.

Oppegard LM, Hamann BL, Streck KR, Ellis KC, Fiedler HP, Khodursky AB, et al. In vivo and in vitro

patterns of the activity of simocyclinone D8, an angucyclinone antibiotic from Streptomyces antibioticus. Antimicrob Agents Chemother. 2009;53:2110–2119.

Verghese J, Nguyen T, Oppegard LM, Seivert LM, Hiasa H, Ellis KC. Flavone-based analogues inspired by the natural product simocyclinone D8 as DNA gyrase inhibitors. Bioorg Med Chem Lett. 2013;23:5874–5877.

Mitton-Fry MJ, Brickner SJ, Hamel JC, Brennan L, Casavant JM, Chen M, et al. Novel quinoline derivatives as inhibitors of bacterial DNA gyrase and topoisomerase IV. Bioorg Med Chem Lett. 2013;23:2955–2961.

Gaskell L. Defining a simplified pharmacophore for simocyclinone D8 inhibition of DNA Gyrase. Master of Pharmaceutical Sciences [Theses]. Virginia Commonwealth University; 2013. Available at Jan 8, 2016.

Huang Z, Lin K, You Q. De novo design of novel DNA-gyrase inhibitors based on 2D molecular fingerprints. Bioorg Med Chem Lett. 2013;23:4166–4171.


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