Abstract
Previous studies have established the essentiality of the bacterial DNA replication process and its requisite enzymes including DNA gyrase and topoisomerase IV. The quinolone class of antibiotics provided a clinical validation of these targets and has been widely used over the past 50 years. A number of more recent examples of these compounds are described herein. Two related, but structurally distinct quinolone-like compounds are also discussed. Non-quinolones, designated novel bacterial type II topoisomerase inhibitors (NBTIs), have been explored and several examples are provided in this work. Successful development of these latter compounds could enhance and extend the clinical utility of bacterial topoisomerase inhibitors beyond the clinically valuable and commercially successful quinolone antibiotics. Bacterial topoisomerase inhibitors should continue to play an important role in the battle against bacterial pathogens for many years to come.
Keywords
- Complicated Urinary Tract Infection
- Potent Antibacterial Activity
- Bacterial Conjunctivitis
- Excellent Antibacterial Activity
- hERG Inhibition
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Adam HJ, Laing NM, King CR, Lulashnyk B, Hoban DJ, Zhanel GG (2009) In vitro activity of nemonoxacin, a novel nonfluorinated quinolone, against 2,440 clinical isolates. Antimicrob Agents Chemother 53:4915–4920
Almer LS, Hoffrage JB, Keller EJ, Flamm RK, Shortridge VD (2004) In vitro and bactericidal activities of ABT-492, a novel fluoroquinolone, against Gram-positive and Gram-negative organisms. Antimicrob Agents Chemother 48:2771–2777
Anderle C, Stieger M, Burrell M, Reinelt S, Maxwell A, Page M, Heide L (2008) Biological activities of novel gyrase inhibitors of the aminocoumarin class. Antimicrob Agents Chemother 52:1982–1990
Angehrn P, Goetschi E, Gmuender H et al (2011) A new DNA gyrase inhibitor subclass of the cyclothialidine family based on a bicyclic dilactam-lactone scaffold synthesis and antibacterial properties. J Med Chem 54:2207–2224
Araake M, Hara T, Watabe H, Nishino T (2002) In vitro antibacterial activity of prulifloxacin, a new oral fluoroquinolone. Jpn J Antibiot 55:778–790
Axten JM, Brooks G, Brown P et al (2004) PCT Int Appl WO004058144
Bax BD, Chan PF, Eggleston DS et al (2010) Type IIA topoisomerase inhibition by a new class of antibacterial agents. Nature 466:935–940
Black MT, Coleman K (2009) New inhibitors of bacterial topoisomerase GyrA/ParC subunits. Curr Opin Investig Drugs 10:804–810
Black MT, Stachyra T, Platel D, Girard AM, Claudon M, Bruneau JM, Miossec C (2008) Mechanism of action of the antibiotic NXL101, a novel nonfluoroquinolone inhibitor of bacterial type II topoisomerases. Antimicrob Agents Chemother 52:3339–3349
Bradbury BJ, Pucci MJ (2008) Recent advances in bacterial topoisomerase inhibitors. Curr Opin Pharmacol 8:574–581
Cambau E, Matrat S, Pan XS, Bettoni RRD, Corbel C, Aubry A, Lascols C, Driot JY, Fisher LM (2009) Target specificity of the new fluoroquinolone besifloxacin in Streptococcus pneumoniae, Staphylococcus aureus and Escherichia coli. J Antimicrob Chemother 63:443–450
Charifson PS, Grillot AL, Grossman TH et al (2008) 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 51:5243–5263
Chu DT, Fernandes PB, Claiborne AK, Shen L, Pernet AG (1988) Structure-activity relationships in quinolone antibacterials: design, synthesis and biological activities of novel isothiazoloquinolones. Drugs Exp Clin Res 14:379–383
Chung DT, Tsai TY, Chen SJ et al (2009) Multiple-dose safety, tolerability, and pharmacokinetics of oral nemonoxacin (TG-873870) in healthy volunteers. Antimicrob Agents Chemother 54:411–417
Collin F, Karkare S, Maxwell A (2011) Exploiting bacterial DNA gyrase as a drug target: current state and perspectives. Appl Microbiol Biotechnol 92:479–497
Covington P, Davenport JM, Andrae D, O’Riordan W, Liverman L, McIntyre G, Almenoff J (2011) Randomized, double-blind, phase II, multicenter study evaluating the safety/tolerability and efficacy of JNJ-Q2, a novel fluoroquinolone, compared with linezolid for treatment of acute bacterial skin and skin structure infection. Antimicrob Agents Chemother 55:5790–5797
Domogala JM, Hagen SE (2003) Structure-activity relationships of the quinolone antibacterials in the new millennium: some things change and some do not. In: Hooper DC, Rubenstein E (eds) Quinolone antimicrobial agents, 3rd edn. ASM Press, Washington, DC
Drlica K, Hiasa H, Kerns R, Malik M, Mustaev A, Zhao X (2000) Quinolones action and resistance updated. Curr Top Med Chem 9:981–998
Drlica K, Malik M, Kerns RJ, Zhao X (2008) Quinolone-mediated bacterial death. Antimicrob Agents Chemother 52:385–392
Eakin AE, Green O, Hales N et al (2012) Pyrrolamide DNA gyrase inhibitors: fragment-based nuclear magnetic resonance screening to identify antibacterial agents. Antimicrob Agents Chemother 56:1240–1246
East SP, White CB, Barker O et al (2009) DNA gyrase (GyrB)/topoisomerase IV (ParE) inhibitors: synthesis and antibacterial activity. Bioor Med Chem Lett 19:894–899
Ellsworth EL, Tran TP, Showalter HDH et al (2006) 3-Aminoquinazolinediones as a new class of antibacterial agents demonstrating excellent antibacterial activity against wild-type and multidrug resistant organisms. J Med Chem 49:6435–6438
Emmerson AM, Jones AM (2003) The quinolones: decades of development and use. J Antimicrob Chemother 51(Suppl S1):13–20
Emrich NC, Heisig A, Stubbings W, Labischinski H, Heisig P (2010) Antibacterial activity of finafloxacin under different pH conditions against isogenic strains of Escherichia coli expressing combinations. J Antimicrob Chemother 65:2530–2533
Fernandez J, Hilliard JJ, Morrow BJ, Melton JL, Flamm RK, Barron AM, Lynch AS (2011) Efficacy of a new fluoroquinolone, JNJ-Q2, in murine models of Staphylococcus aureus and Streptococcus pneumoniae skin, respiratory, and systemic infections. Antimicrob Agents Chemother 55:5522–5528
Fritsche TR, Biedenbach DJ, Jones RN (2009) Antimicrobial activity of prulifloxacin tested against a worldwide collection of gastroenteritis-producing pathogens, including those causing traveler’s diarrhea. Antimicrob Agents Chemother 53:1221–1224
Giannarini G, Tascini C, Selli C (2009) Prulifloxacin: clinical studies of a broad-spectrum quinolone agent. Future Microbiol 4:13–24
Grossman TH, Bartels DJ, Mullin S (2007) Dual targeting of GyrB and ParE by a novel aminobenzimidazole class of antibacterial compounds. Antimicrob Agents Chemother 5:657–666
Haas W, Pillar CM, Zurenko GM, Lee JC, Brunner LS, Morris TW (2009) Besifloxacin, a novel fluoroquinolone, has broad-spectrum in vitro activity against aerobic and anaerobic bacteria. Antimicrob Agents Chemother 53:3552–3560
Heide L (2009) Genetic engineering of antibiotic biosynthesis for the generation of new aminocoumarins. Biotechnol Adv 27:1006–1014
Higgins PG, Stubbings W, Wisplinghoff H, Seifert H (2010) Activity of the investigational fluoroquinolone finafloxacin against ciprofloxacin-sensitive and -resistant Acinetobacter baumannii. Antimicrob Agents Chemother 54:1613–1615
Hoshino K, Inoue K, Murakami Y, Kurosaka Y, Namba K, Kashimoto Y, Uoyama S, Okumura R, Higuchi S, Otani T (2008) In vitro and in vivo antibacterial activities of DC-159a, a new fluoroquinolone. Antimicrob Agents Chemother 52:65–70
Huband MD, Cohen MA, Zurack M et al (2007) In vitro and in vivo activities of PD 0305970 and PD 0326448, new bacterial gyrase/topoisomerase inhibitors with potent antibacterial activities versus multidrug-resistant Gram-positive and fastidious organism groups. Antimicrob Agents Chemother 51:1191–1201
Jones RN, Fritsche TR, Sader HS (2008) Antimicrobial activity of DC-159a, a new fluoroquinolone, against 1,149 recently collected clinical isolates. Antimicrob Agents Chemother 52:3763–3775
Keam SJ, Perry CM (2004) Prulifloxacin. Drugs 64:2221–2234
Kim EJ, Shin WH, Kim KS, Han SS (2004) Safety pharmacology of DW-224a, a novel fluoroquinolone antibiotic agent. Drug Chem Toxicol 27:295–307
Kuramoto Y, Ohshita Y, Yoshida J, Yazaki A, Shiro M, Koike T (2003) A novel antibacterial 8-chloroquinolone with a distorted orientation of the N1-(5-amino-2,4-difluorophenyl) group. J Med Chem 46:1905–1917
Kwon AR, Min YH, Ryu JM, Choi DR, Shim MJ, Choi EC (2006) In vitro and in vivo activities of DW-224a, a novel fluoroquinolone antibiotic agent. J Antimicrob Chemother 56:684–688
Lawrence L, Benedict M, Hart J, Hawkins A, Li D, Medlock M, Hopkins S, Burak E (2011) Pharmacokinetics (PK) and safety of single doses of delafloxacin administered intravenously in healthy human subjects. In: 51st interscience conference on antimicrobial agents and chemotherapy, abstr A2-045a
Lesher GY, Froelic EJ, Gruett MD, Bailey JH, Brundage RP (1962) 1,8-Naphthyridine derivatives. A new class of therapeutic agents. J Med Chem 91:1063–1065
Levasseur, P, Delachaume C, Lowther J, Hodgson J (2005) Minimum inhibitory concentrations (MIC) and mutation prevention concentrations (MPC) of NXL101, a novel topoisomerase IV inhibitor, against Staphylococcus aureus including multi-resistant strains. In: 45th interscience conference on antimicrobial agents and chemotherapy, abstr F-507
Levasseur, P, Girard AM, Lowther J (2007) Efficacy of oral NXL101, a novel topoisomerase inhibitor, against fluoroquinolone-susceptible (FQS) and -resistant (FQR) Streptococcus pneumoniae (Sp) strains in a mouse pneumonia model. In: 47th interscience conference on antimicrobial agents and chemotherapy, abstr F1-2125
Lin L, Chang LW, Tsai CY, Hsu CH, Chung DT, Aronstein WS, Ajayi F, Kuzmak B, Lyon RA (2010) Dose escalation study of the safety, tolerability, and pharmacokinetics of nemonoxacin (TG-873870), a novel potent broad-spectrum nonfluorinated quinolone, in healthy volunteers. Antimicrob Agents Chemother 54:405–410
Lowther J, Levasseur P, Girard AM, Delachaume C, Borgonovi M, Hodgson J (2006) Efficacy of NXL101, a novel topoisomerase inhibitor, against multi-resistant Staphylococcus aureus in murine septicaemia and thigh muscle infections. In: 46th interscience conference on antimicrobial agents and chemotherapy, abstr F1-1999
Mani N, Gross CH et al (2006) In vitro characterization of the antibacterial spectrum of novel bacterial type II topoisomerase inhibitors of the aminobenzimidazole class. Antimicrob Agents Chemother 50:1228–1237
Matera MG (2006) Pharmacologic characteristics of prulifloxacin. Pulm Pharmacol Ther 19(Suppl 1):20–29
Mitscher LA (2005) Bacterial topoisomerase inhibitors: quinolone and pyridone antibacterial agents. Chem Rev 105:559–592
Morrow BJ, He W, Amsler KM, Foleno BD, Macielag MJ, Lynch AS, Bush K (2010) In vitro antibacterial activities of JNJ-Q2, a new broad-spectrum fluoroquinolone. Antimicrob Agents Chemother 54:1955–1964
Morrow BJ, Abbanat D, Baum EZ, Crespo-Carbone SM, Davies TA, He W, Shang W, Queenan AM, Lynch AS (2011) Antistaphylococcal activities of the new fluoroquinolone JNJ-Q2. Antimicrob Agents Chemother 55:5512–5521
Nilius AM, Shen LL, Hensey-Rudloff D, Almer LS, Beyer JM, Balli DJ, Cai Y, Flamm RK (2003) In vitro antibacterial potency and spectrum of ABT-492, a new fluoroquinolone. Antimicrob Agents Chemother 47:3260–3269
Oppegard LM, Hamann BL, Streck KR, Ellis KC, Fiedler HP, Khodursky AB, Hiasa H (2009) In vivo and in vitro patterns of the activity of simocyclinone D8, an angucyclinone antibiotic from Streptomyces antibioticus. Antimicrob Agents Chemother 53:2110–2119
Owens RC Jr, Ambrose PG (2000) Clinical use of the fluoroquinolones. Med Clin North Am 84:1447–1469
Owens RC Jr, Ambrose PG (2005) Antimicrobial safety: focus on quinolones. Clin Infect Dis 41(Suppl 2):S144–S157
Pan XS, Gould KA, Fisher LM (2009) Probing the differential interactions of quinazolinedione PD 0305970 and quinolones with gyrase and topoisomerase IV. Antimicrob Agents Chemother 53:3822–3831
Park HS, Kim HJ, Seol MJ, Choi DR, Choi EC, Kwak JH (2006) In vitro and in vivo antibacterial activities of DW-224a, a new fluoronaphthyridone. Antimicrob Agents Chemother 50:2261–2264
Pucci MJ, Cheng J, Podos SD, Thoma CL, Thanassi JA, Buechter DD, Mushtaq G, Vigliotti GA Jr, Bradbury BJ, Deshpande M (2007) In vitro and in vivo antibacterial activities of heteroaryl isothiazolones against resistant Gram-positive pathogens. Antimicrob Agents Chemother 51:1259–1267
Pucci MJ, Podos SD, Thanassi JA, Leggio MJ, Bradbury BJ, Deshpande M (2011) In vitro and in vivo profiles of ACH-702, an isothiazoloquinolone, against bacterial pathogens. Antimicrob Agents Chemother 55:2860–2871
Rafailidis PI, Polyzos KA, Sgouros K, Falagas ME (2011) Prulifloxacin: a review focusing on its use beyond respiratory and urinary tract infections. Int J Antimicrob Agents 37:283–290
Reck F, Alm R, Brassil P et al (2011) Novel N-linked aminopiperidine inhibitors of bacterial topoisomerase type II: broad-spectrum antibacterial agents with reduced hERG activity. J Med Chem 54:7834–7847
Rubenstein E (2001) History of quinolones and their side effects. Chemother 47(Suppl 3):3–8
Ryder NS (2010) Discontinued drugs in 2008: anti-infectives. Expert Opin Investig Drugs 19:1–21
Sherer BA et al (2011) Pyrrolamide DNA gyrase inhibitors: optimization of antibacterial activity and efficacy. Bioorg Med Chem Lett 21:7416–7420
Tari LW, Bensen D, Tzross M et al (2011a) The discovery of potent, dual targeting pyrrolopyrimidine inhibitors of bacterial DNA gyrase B and topoisomerase IV with broad spectrum antibacterial activity. In: 51st interscience conference on antimicrobial agents and chemotherapy, abstr F1-1837
Tari LW, Bensen D, Tzross M et al (2011b) The discovery of novel, dual targeting inhibitors of bacterial DNA gyrase B and topoisomerase IV using pharmacophore-based crystallographic fragment screening. In: 51st interscience conference on antimicrobial agents and chemotherapy, abstr F2-1872
Tarral A, Rangaraju M, Merdjan H, Girard AM, Delachaume C, Lowther J (2007) Plasma bactericidal activity of NXL101 in healthy volunteers after single intravenous administration of 50 to 700 mg. In: 47th interscience conference on antimicrobial agents and chemotherapy, abstr A808
Tepedino ME, Heller WH, Usner DW, Brunner LS, Morris TW, Haas W, Paterno MR, Comstock T (2009) Phase III efficacy and safety study of besifloxacin ophthalmic suspension 0.6% in the treatment of bacterial conjunctivitis. Curr Med Res Opin 25:1159–1169
Wang Q, Lucien E, Hashimoto A et al (2007) Isothiazoloquinolones with enhanced antistaphylococcal activities against multi-drug resistant strains: effects of structural modifications at the 6-, 7-, and 8-positions. J Med Chem 50:199–210
Wang X, Zhao X, Malik M, Drlica K (2010) Contribution of reactive oxygen species to pathways of quinolone-mediated bacterial cell death. J Antimicrob Chemother 65:520–524
Wiles JA, Bradbury BJ, Pucci MJ (2010) New quinolone antibiotics: a survey of the literature from 2005 to 2010. Expert Opin Ther Patents 20:1295–1319
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Pucci, M.J., Wiles, J.A. (2014). Bacterial Topoisomerase Inhibitors: Quinolones and Beyond. In: Marinelli, F., Genilloud, O. (eds) Antimicrobials. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-39968-8_16
Download citation
DOI: https://doi.org/10.1007/978-3-642-39968-8_16
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-39967-1
Online ISBN: 978-3-642-39968-8
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)