Abstract
DNA gyrase is a clinically validated drug target, currently targeted only by fluoroquinolone class of antibacterials. However, owing to increasing drug resistance as well as a concomitant reduction in the availability of newer classes of antibiotics, fluoroquinolones are increasingly being over-utilized in order to treat serious infections, including multi-drug resistant tuberculosis. This, in turn, increases the probability of resistance to fluoroquinolones, which is mediated by a single amino acid change in gyrA, leading to class-wide resistance. In this review, we provide an overview of the recent progress in identifying novel scaffolds which target DNA gyrase and provide an update on their discovery and development status.
Keywords: Mycobacterium tuberculosis, DNA gyrase, Fluoroquinolones, Aminocoumarins, Antibacterials, Pathogen.
Graphical Abstract
[2]
Payne, D.J.; Gwynn, M.N.; Holmes, D.J.; Pompliano, D.L. Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat. Rev. Drug Discov., 2007, 6(1), 29-40. [http://dx.doi.org/ 10.1038/nrd2201]. [PMID: 17159923].
[3]
Watanabe, J.; Nakada, N.; Sawairi, S.; Shimada, H.; Ohshima, S.; Kamiyama, T.; Arisawa, M. Cyclothialidine, a novel DNA gyrase inhibitor. I. Screening, taxonomy, fermentation and biological activity. J. Antibiot. (Tokyo), 1994, 47(1), 32-36. [http://dx.doi.org/ 10.7164/antibiotics.47.32]. [PMID: 8119859].
[4]
Ferrero, L.; Cameron, B.; Manse, B.; Lagneaux, D.; Crouzet, J.; Famechon, A.; Blanche, F. Cloning and primary structure of Staphylococcus aureus DNA topoisomerase IV: a primary target of fluoroquinolones. Mol. Microbiol., 1994, 13(4), 641-653. [http://dx.doi.org/10.1111/j.1365-2958.1994.tb00458.x]. [PMID: 7997176].
[5]
Barančoková, M.; Kikelj, D.; Ilaš, J. Recent progress in the discovery and development of DNA gyrase B inhibitors. Future Med. Chem., 2018, 10(10), 1207-1227. [http://dx.doi.org/10.4155/fmc-2017-0257]. [PMID: 29787300].
[6]
Chopra, S.; Matsuyama, K.; Tran, T.; Malerich, J.P.; Wan, B.; Franzblau, S.G.; Lun, S.; Guo, H.; Maiga, M.C.; Bishai, W.R.; Madrid, P.B. Evaluation of gyrase B as a drug target in Mycobacterium tuberculosis. J. Antimicrob. Chemother., 2012, 67(2), 415-421. [http://dx.doi.org/10.1093/jac/dkr449]. [PMID: 22052686].
[7]
Pommier, Y.; Pourquier, P.; Fan, Y.; Strumberg, D. Mechanism of action of eukaryotic DNA topoisomerase I and drugs targeted to the enzyme. Biochim. Biophys. Acta, 1998, 1400(1-3), 83-105. [http://dx.doi.org/10.1016/S0167-4781(98)00129-8]. [PMID: 9748515].
[8]
Aubry, A.; Pan, X.S.; Fisher, L.M. Mycobacterium tuberculosis DNA gyrase: interaction with quinolones and correlation with antimycobacterial drug activity. Antimicrob. Agents Chemother., 2004, 48(4), 1281-1288.
[9]
Ji, B.; Lounis, N.; Truffot-Pernot, C.; Grosset, J. In vitro and in vivo activities of levofloxacin against Mycobacterium tuberculosis. Antimicrob. Agents Chemother., 1995, 39(6), 1341-1344. [http://dx.doi.org/10.1128/AAC.39.6.1341]. [PMID: 7574527].
[10]
Dong, Y.; Xu, C.; Zhao, X.; Domagala, J.; Drlica, K. Fluoroquinolone action against mycobacteria: effects of C-8 substituents on growth, survival, and resistance. Antimicrob. Agents Chemother., 1998, 42(11), 2978-2984. [http://dx.doi.org/10.1128/AAC.42. 11.2978]. [PMID: 9797236].
[11]
Dong, Y.; Zhao, X.; Kreiswirth, B.N.; Drlica, K. Mutant prevention concentration as a measure of antibiotic potency: studies with clinical isolates of Mycobacterium tuberculosis. Antimicrob. Agents Chemother., 2000, 44(9), 2581-2584. [http://dx.doi.org/10.1128/ AAC.44.9.2581-2584.2000]. [PMID: 10952625].
[12]
Yoshimatsu, T.; Nuermberger, E.; Tyagi, S.; Chaisson, R.; Bishai, W.; Grosset, J. Bactericidal activity of increasing daily and weekly doses of moxifloxacin in murine tuberculosis. Antimicrob. Agents Chemother., 2002, 46(6), 1875-1879. [http://dx.doi.org/10.1128/ AAC.46.6.1875-1879.2002]. [PMID: 12019103].
[13]
Mdluli, K.; Ma, Z. Mycobacterium tuberculosis DNA gyrase as a target for drug discovery. Infect. Disord. Drug Targets, 2007, 7(2), 159-168. [http://dx.doi.org/10.2174/187152607781001763]. [PMID: 17970226].
[14]
Tomioka, H.; Sato, K.; Shimizu, T.; Sano, C. Anti-Mycobacterium tuberculosis activities of new fluoroquinolones in combination with other antituberculous drugs. J. Infect., 2002, 44(3), 160-165. [http://dx.doi.org/10.1053/jinf.2002.0973]. [PMID: 12099742].
[15]
Alvirez-Freites, E.J.; Carter, J.L.; Cynamon, M.H. In vitro and in vivo activities of gatifloxacin against Mycobacterium tuberculosis. Antimicrob. Agents Chemother., 2002, 46(4), 1022-1025. [http://dx.doi.org/10.1128/AAC.46.4.1022-1025.2002]. [PMID: 11897584].
[16]
Maxwell, A.; Lawson, D.M. The ATP-binding site of type II topoisomerases as a target for antibacterial drugs. Curr. Top. Med. Chem., 2003, 3(3), 283-303. [http://dx.doi.org/10.2174/ 1568026033452500]. [PMID: 12570764].
[17]
Gormley, N.A.; Orphanides, G.; Meyer, A.; Cullis, P.M.; Maxwell, A. The interaction of coumarin antibiotics with fragments of DNA gyrase B protein. Biochemistry, 1996, 35(15), 5083-5092. [http://dx.doi.org/10.1021/bi952888n]. [PMID: 8664301].
[18]
Holdgate, G.A.; Tunnicliffe, A.; Ward, W.H.; Weston, S.A.; Rosenbrock, G.; Barth, P.T.; Taylor, I.W.; Pauptit, R.A.; Timms, D. The entropic penalty of ordered water accounts for weaker binding of the antibiotic novobiocin to a resistant mutant of DNA gyrase: a thermodynamic and crystallographic study. Biochemistry, 1997, 36(32), 9663-9673. [http://dx.doi.org/10.1021/bi970294+]. [PMID: 9245398].
[19]
Kocagöz, T.; Hackbarth, C.J.; Unsal, I.; Rosenberg, E.Y.; Nikaido, H.; Chambers, H.F. Gyrase mutations in laboratory-selected, fluoroquinolone-resistant mutants of Mycobacterium tuberculosis H37Ra. Antimicrob. Agents Chemother., 1996, 40(8), 1768-1774. [http://dx.doi.org/10.1128/AAC.40.8.1768]. [PMID: 8843279].
[20]
Sherer, B.A.; Hull, K.; Green, O.; Basarab, G.; Hauck, S.; Hill, P.; Loch, J.T., III; Mullen, G.; Bist, S.; Bryant, J.; Boriack-Sjodin, A.; Read, J.; DeGrace, N.; Uria-Nickelsen, M.; Illingworth, R.N.; Eakin, A.E. Pyrrolamide DNA gyrase inhibitors: optimization of antibacterial activity and efficacy. Bioorg. Med. Chem. Lett., 2011, 21(24), 7416-7420. [http://dx.doi.org/10.1016/j.bmcl.2011.10.010]. [PMID: 22041057].
[21]
Ronkin, S.M.; Badia, M.; Bellon, S.; Grillot, A.L.; Gross, C.H.; Grossman, T.H.; Mani, N.; Parsons, J.D.; Stamos, D.; Trudeau, M.; Wei, Y.; Charifson, P.S. Discovery of pyrazolthiazoles as novel and potent inhibitors of bacterial gyrase. Bioorg. Med. Chem. Lett., 2010, 20(9), 2828-2831. [http://dx.doi.org/10.1016/j.bmcl. 2010.03.052]. [PMID: 20356737].
[22]
Oblak, M.; Grdadolnik, S.G.; Kotnik, M.; Jerala, R.; Filipic, M.; Solmajer, T. In silico fragment-based discovery of indolin-2-one analogues as potent DNA gyrase inhibitors. Bioorg. Med. Chem. Lett., 2005, 15(23), 5207-5210. [http://dx.doi.org/10.1016/ j.bmcl.2005.08.068]. [PMID: 16203145].
[23]
Boehm, H.J.; Boehringer, M.; Bur, D.; Gmuender, H.; Huber, W.; Klaus, W.; Kostrewa, D.; Kuehne, H.; Luebbers, T.; Meunier-Keller, N.; Mueller, F. Novel inhibitors of DNA gyrase: 3D structure based biased needle screening, hit validation by biophysical methods, and 3D guided optimization. A promising alternative to random screening. J. Med. Chem., 2000, 43(14), 2664-2674. [http://dx.doi.org/10.1021/jm000017s]. [PMID: 10893304].
[24]
Charifson, P.S.; Grillot, A.L.; Grossman, T.H.; Parsons, J.D.; Badia, M.; Bellon, S.; Deininger, D.D.; Drumm, J.E.; Gross, C.H.; LeTiran, A.; Liao, Y.; Mani, N.; Nicolau, D.P.; Perola, E.; Ronkin, S.; Shannon, D.; Swenson, L.L.; Tang, Q.; Tessier, P.R.; Tian, S.K.; Trudeau, M.; Wang, T.; Wei, Y.; Zhang, H.; Stamos, D. Novel dual-targeting benzimidazole urea inhibitors of DNA gyrase and topoisomerase IV possessing potent antibacterial activity: intelligent design and evolution through the judicious use of structure-guided design and structure-activity relationships. J. Med. Chem., 2008, 51(17), 5243-5263. [http://dx.doi.org/10.1021/jm800318d]. [PMID: 18690678].
[25]
Brvar, M.; Perdih, A.; Renko, M.; Anderluh, G.; Turk, D.; Solmajer, T. Structure-based discovery of substituted 4,5′-bithiazoles as novel DNA gyrase inhibitors. J. Med. Chem., 2012, 55(14), 6413-6426. [http://dx.doi.org/10.1021/jm300395d]. [PMID: 22731783].
[26]
Shirude, P.S.; Madhavapeddi, P.; Tucker, J.A.; Murugan, K.; Patil, V.; Basavarajappa, H.; Raichurkar, A.V.; Humnabadkar, V.; Hussein, S.; Sharma, S.; Ramya, V.K.; Narayan, C.B.; Balganesh, T.S.; Sambandamurthy, V.K. Aminopyrazinamides: novel and specific GyrB inhibitors that kill replicating and nonreplicating Mycobacterium tuberculosis. ACS Chem. Biol., 2013, 8(3), 519-523. [http://dx.doi.org/10.1021/cb300510w]. [PMID: 23268609].
[27]
Jeankumar, V.U.; Renuka, J.; Santosh, P.; Soni, V.; Sridevi, J.P.; Suryadevara, P.; Yogeeswari, P.; Sriram, D. Thiazole-aminopiperidine hybrid analogues: design and synthesis of novel Mycobacterium tuberculosis GyrB inhibitors. Eur. J. Med. Chem., 2013, 70, 143-153. [http://dx.doi.org/10.1016/j.ejmech.2013.09. 025]. [PMID: 24148991].
[28]
Karkare, S.; Chung, T.T.; Collin, F.; Mitchenall, L.A.; McKay, A.R.; Greive, S.J.; Meyer, J.J.; Lall, N.; Maxwell, A. The naphthoquinone diospyrin is an inhibitor of DNA gyrase with a novel mechanism of action. J. Biol. Chem., 2013, 288(7), 5149-5156. [http://dx.doi.org/10.1074/jbc.M112.419069]. [PMID: 23275348].
[29]
Jeankumar, V.U.; Renuka, J.; Kotagiri, S.; Saxena, S.; Kakan, S.S.; Sridevi, J.P.; Yellanki, S.; Kulkarni, P.; Yogeeswari, P.; Sriram, D. Gyrase ATPase domain as an antitubercular drug discovery platform: structure-based design and lead optimization of nitrothiazolyl carboxamide analogues. ChemMedChem, 2014, 9(8), 1850-1859. [http://dx.doi.org/10.1002/cmdc.201402035]. [PMID: 24962352].
[30]
Jeankumar, V.U.; Renuka, J.; Pulla, V.K.; Soni, V.; Sridevi, J.P.; Suryadevara, P.; Shravan, M.; Medishetti, R.; Kulkarni, P.; Yogeeswari, P.; Sriram, D. Development of novel N-linked aminopiperidine-based mycobacterial DNA gyrase B inhibitors: scaffold hopping from known antibacterial leads. Int. J. Antimicrob. Agents, 2014, 43(3), 269-278. [http://dx.doi.org/10.1016/j.ijantimicag. 2013.12.006]. [PMID: 24434114].
[31]
Godbole, A.A.; Ahmed, W.; Bhat, R.S.; Bradley, E.K.; Ekins, S.; Nagaraja, V. Inhibition of Mycobacterium tuberculosis topoisomerase I by m-AMSA, a eukaryotic type II topoisomerase poison. Biochem. Biophys. Res. Commun., 2014, 446(4), 916-920. [http://dx.doi.org/10.1016/j.bbrc.2014.03.029]. [PMID: 24642256].
[32]
Reddy, K.I.; Srihari, K.; Renuka, J.; Sree, K.S.; Chuppala, A.; Jeankumar, V.U.; Sridevi, J.P.; Babu, K.S.; Yogeeswari, P.; Sriram, D. An efficient synthesis and biological screening of benzofuran and benzo[d]isothiazole derivatives for Mycobacterium tuberculosis DNA GyrB inhibition. Bioorg. Med. Chem., 2014, 22(23), 6552-6563. [http://dx.doi.org/10.1016/j.bmc.2014.10.016]. [PMID: 25456076].
[33]
Renuka, J.; Reddy, K.I.; Srihari, K.; Jeankumar, V.U.; Shravan, M.; Sridevi, J.P.; Yogeeswari, P.; Babu, K.S.; Sriram, D. Design, synthesis, biological evaluation of substituted benzofurans as DNA gyraseB inhibitors of Mycobacterium tuberculosis. Bioorg. Med. Chem., 2014, 22(17), 4924-4934. [http://dx.doi.org/10.1016/ j.bmc.2014.06.041]. [PMID: 25129171].
[34]
Medapi, B.; Renuka, J.; Saxena, S.; Sridevi, J.P.; Medishetti, R.; Kulkarni, P.; Yogeeswari, P.; Sriram, D. Design and synthesis of novel quinoline-aminopiperidine hybrid analogues as Mycobacterium tuberculosis DNA gyraseB inhibitors. Bioorg. Med. Chem., 2015, 23(9), 2062-2078. [http://dx.doi.org/10.1016/j.bmc.2015.03. 004]. [PMID: 25801151].
[35]
Saxena, S.; Samala, G.; Renuka, J.; Sridevi, J.P.; Yogeeswari, P.; Sriram, D. Development of 2-amino-5-phenylthiophene-3-carboxamide derivatives as novel inhibitors of Mycobacterium tuberculosis DNA GyrB domain. Bioorg. Med. Chem., 2015, 23(7), 1402-1412. [http://dx.doi.org/10.1016/j.bmc.2015.02.032]. [PMID: 25766629].
[36]
Medapi, B.; Suryadevara, P.; Renuka, J.; Sridevi, J.P.; Yogeeswari, P.; Sriram, D. 4-Aminoquinoline derivatives as novel Mycobacterium tuberculosis GyrB inhibitors: Structural optimization, synthesis and biological evaluation. Eur. J. Med. Chem., 2015, 103, 1-16. [http://dx.doi.org/10.1016/j.ejmech.2015.06.032]. [PMID: 26318054].
[37]
Chandran, M.; Renuka, J.; Sridevi, J.P.; Pedgaonkar, G.S.; Asmitha, V.; Yogeeswari, P.; Sriram, D. Benzothiazinone-piperazine derivatives as efficient Mycobacterium tuberculosis DNA gyrase inhibitors. Int. J. Mycobacteriol., 2015, 4(2), 104-115. [http://dx. doi.org/10.1016/j.ijmyco.2015.02.002]. [PMID: 26972878].
[38]
Jeankumar, V.U.; Saxena, S.; Vats, R.; Reshma, R.S.; Janupally, R.; Kulkarni, P.; Yogeeswari, P.; Sriram, D. Structure-Guided Discovery of Antitubercular Agents That Target the Gyrase ATPase Domain. ChemMedChem, 2016, 11(5), 539-548. [http://dx.doi.org/ 10.1002/cmdc.201500556]. [PMID: 26805396].
[39]
Sipos, A.; Pató, J.; Székely, R.; Hartkoorn, R.C.; Kékesi, L.; Őrfi, L.; Szántai-Kis, C.; Mikušová, K.; Svetlíková, Z.; Korduláková, J.; Nagaraja, V.; Godbole, A.A.; Bush, N.; Collin, F.; Maxwell, A.; Cole, S.T.; Kéri, G. Lead selection and characterization of antitubercular compounds using the Nested Chemical Library. Tuberculosis (Edinb.), 2015, 95(Suppl. 1), S200-S206. [http://dx.doi.org/ 10.1016/j.tube.2015.02.028]. [PMID: 25801335].
[40]
Sandhaus, S.; Annamalai, T.; Welmaker, G.; Houghten, R.A.; Paz, C.; Garcia, P.K.; Andres, A.; Narula, G.; Rodrigues Felix, C.; Geden, S.; Netherton, M.; Gupta, R.; Rohde, K.H.; Giulianotti, M.A.; Tse-Dinh, Y.C. Small-Molecule Inhibitors Targeting Topoisomerase I as Novel Antituberculosis Agents. Antimicrob. Agents Chemother., 2016, 60(7), 4028-4036. [http://dx.doi.org/10.1128/ AAC.00288-16]. [PMID: 27114277].
[41]
Kale, M.G.; Raichurkar, A. P, S.H.; Waterson, D.; McKinney, D.; Manjunatha, M.R.; Kranthi, U.; Koushik, K.; Jena, Lk.; Shinde, V.; Rudrapatna, S.; Barde, S.; Humnabadkar, V.; Madhavapeddi, P.; Basavarajappa, H.; Ghosh, A.; Ramya, V.K.; Guptha, S.; Sharma, S.; Vachaspati, P.; Kumar, K.N.; Giridhar, J.; Reddy, J.; Panduga, V.; Ganguly, S.; Ahuja, V.; Gaonkar, S.; Kumar, C.N.; Ogg, D.; Tucker, J.A.; Boriack-Sjodin, P.A.; de Sousa, S.M.; Sambandamurthy, V.K.; Ghorpade, S.R. Thiazolopyridine ureas as novel antitubercular agents acting through inhibition of DNA Gyrase B. J. Med. Chem., 2013, 56(21), 8834-8848. [http://dx.doi.org/10.1021/ jm401268f]. [PMID: 24088190].
[42]
P, S.H.; Solapure, S.; Mukherjee, K.; Nandi, V.; Waterson, D.; Shandil, R.; Balganesh, M.; Sambandamurthy, V.K.; Raichurkar, A.K.; Deshpande, A.; Ghosh, A.; Awasthy, D.; Shanbhag, G.; Sheikh, G.; McMiken, H.; Puttur, J.; Reddy, J.; Werngren, J.; Read, J.; Kumar, M.; R, M.; Chinnapattu, M.; Madhavapeddi, P.; Manjrekar, P.; Basu, R.; Gaonkar, S.; Sharma, S.; Hoffner, S.; Humnabadkar, V.; Subbulakshmi, V.; Panduga, V. Optimization of pyrrolamides as mycobacterial GyrB ATPase inhibitors: structure-activity relationship and in vivo efficacy in a mouse model of tuberculosis. Antimicrob. Agents Chemother., 2014, 58(1), 61-70. [http://dx.doi.org/10.1128/AAC.01751-13]. [PMID: 24126580].
[43]
Blanco, D.; Perez-Herran, E.; Cacho, M.; Ballell, L.; Castro, J.; González Del Río, R.; Lavandera, J.L.; Remuiñán, M.J.; Richards, C.; Rullas, J.; Vázquez-Muñiz, M.J.; Woldu, E.; Zapatero-González, M.C.; Angulo-Barturen, I.; Mendoza, A.; Barros, D. Mycobacterium tuberculosis gyrase inhibitors as a new class of antitubercular drugs. Antimicrob. Agents Chemother., 2015, 59(4), 1868-1875. [http://dx.doi.org/10.1128/AAC.03913-14]. [PMID: 25583730].
[44]
Locher, C.P.; Jones, S.M.; Hanzelka, B.L.; Perola, E.; Shoen, C.M.; Cynamon, M.H.; Ngwane, A.H.; Wiid, I.J.; van Helden, P.D.; Betoudji, F.; Nuermberger, E.L.; Thomson, J.A. A novel inhibitor of gyrase B is a potent drug candidate for treatment of tuberculosis and nontuberculosis mycobacterial infections. Antimicrob. Agents Chemother., 2015, 59(3), 1455-1465. [http://dx.doi.org/10.1128/ AAC.04347-14]. [PMID: 25534737].
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