Skip to main content
SpringerLink
Log in
Book cover

Antimicrobial Compounds pp 149–175Cite as

The Cornerstone of Nucleic Acid-Affecting Antibiotics in Bacteria

  • Chapter
  • First Online:

Abstract

Relatively few new antibiotics targeted against nucleic acids have been developed in the last 50 years. Rifamycins and a wide group of related microbial compounds block RNA synthesis by specific inhibition of bacterial RNA polymerase without interacting with mammalian analog enzymes. Others, such as actinomycins or doxorubicin, interfere with transcription in both bacterial and mammalian systems and may be used as antitumor drugs because the fast growth favors a higher percentage of death in malignant cells respect to normal counterparts. Another group of antibiotics interferes with DNA synthesis by acting on the bacterial DNA gyrase involved in the mechanism of replication of closed-circular DNA. Most members of this group, including aminocoumarin antibiotics, work by binding to the ATPase active site located on one subunit of the gyrase enzyme. Moreover, antibiotics effective against mammalian topoisomerases or able to prevent normal DNA distribution into daughter cells are being also used as antineoplastic drugs. In spite of the wide variety of mechanisms classically invoked to explain the primary action of antibacterial drugs, a new view is emerging whereby the killing damage behind all major classes of antibiotics appears to stem from the generation of destructive molecules that fatally damage nucleic acids through a long chain of cellular events.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Ackermann G, Löffler B, Adler D et al (2004) In vitro activity of OPT-80 against Clostridium difficile. Antimicrob Agents Chemother 48:2280–2282

    Article  PubMed  CAS  Google Scholar 

  • Adelman K, Yuzenkova J, La Porta A et al (2004) Molecular mechanism of transcription inhibition by peptide antibiotic microcin J25. Mol Cell 14:753–762

    Article  PubMed  CAS  Google Scholar 

  • Allan RK, Mok D, Ward BK et al (2006) Modulation of chaperone function and cochaperone interaction by novobiocin in the C-terminal domain of Hsp90: evidence that coumarin antibiotics disrupt Hsp90 dimerization. J Biol Chem 281:7161–7171

    Article  PubMed  CAS  Google Scholar 

  • Anderle C, Stieger M, Burrell M et al (2008) Biological activities of novel gyrase inhibitors of the aminocoumarin class. Antimicrob Agents Chemother 52:1982–1990

    Article  PubMed  CAS  Google Scholar 

  • Andrez JC (2009) Mitomycins syntheses: a recent update. Beilstein J Org Chem 5:1–36. doi:10.3762/bjoc.5.33

    Article  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Artsimovitch I, Seddon J, Sears P (2012) Fidaxomicin is an inhibitor of the initiation of bacterial RNA synthesis. Clin Infect Dis 55:S127–S131

    Article  PubMed  CAS  Google Scholar 

  • Barbachyn MR (2008) Recent advances in the discovery of hybrid antibacterial agents. Ann Rep Med Chem 43:281–290

    Article  CAS  Google Scholar 

  • Bayro M, Mukhopadhyay J, Swapna GVT et al (2003) Structure of antibacterial peptide microcin J25: a 21-residue lariat proto-knot. J Am Chem Soc 125:12382–12383

    Article  PubMed  CAS  Google Scholar 

  • Belogurov G, Vassylyeva M, Sevostyanova A et al (2009) Transcription inactivation through local refolding of the RNA polymerase structure. Nature 45:332–335

    Article  Google Scholar 

  • Bradner WT (2001) Mitomycin C: a clinical update. Cancer Treat Rev 27:35–50

    Article  PubMed  CAS  Google Scholar 

  • Bramann EL, Willenberg HS, Hildebrandt B et al (2013) Griseofulvin inhibits the growth of adrenocortical cancer cells in vitro. Horm Metab Res 45:297–300

    Google Scholar 

  • Brvar M, Perdih A, Renko M et al (2012) Structure-based discovery of substituted 4,5′-bithiazoles as novel DNA gyrase inhibitors. J Med Chem 55:6413–6426

    Article  PubMed  CAS  Google Scholar 

  • Campbell E, Korzheva N, Mustaev A et al (2001) Structural mechanism for rifampicin inhibition of bacterial RNA polymerase. Cell 104:901–912

    Article  PubMed  CAS  Google Scholar 

  • Campbell E, Pavlova O, Zenkin N et al (2005) Structural, functional, and genetic analysis of sorangicin inhibition of bacterial RNA polymerase. EMBO J 24:674–682

    Article  PubMed  CAS  Google Scholar 

  • Casely-Hayford MA, Pors K, James CH et al (2005) Design and synthesis of a DNA-crosslinking azinomycin analogue. Org Biomol Chem 3:3585–3589

    Article  PubMed  CAS  Google Scholar 

  • Chan YC, Friedlander SF (2004) New treatments for Tinea capitis. Curr Opin Infect Dis 17:97–103

    Article  PubMed  CAS  Google Scholar 

  • Chaudhuri AR, Luduena RF (1996) Griseofulvin: a novel interaction with bovine brain tubulin. Biochem Pharmacol 51:903–909

    Article  PubMed  CAS  Google Scholar 

  • Chen C, Song F, Wang Q et al (2012) A marine-derived Streptomyces sp. MS449 produces high yield of actinomycin X2 and actinomycin D with potent anti-tuberculosis activity. Appl Microbiol Biotechnol 9:919–927

    Article  Google Scholar 

  • Cramer P (2002) Multisubunit RNA polymerases. Curr Opin Struct Biol 12:89–97

    Article  PubMed  CAS  Google Scholar 

  • Czymmek KJ, Bourett TM, Shao Y et al (2005) Live-cell imaging of tubulin in the filamentous fungus Magnaporthe grisea treated with anti-microtubule and anti-microfilament agents. Protoplasma 225:23–32

    Article  PubMed  CAS  Google Scholar 

  • Darst S (2001) Bacterial RNA polymerase. Curr Opin Struct Biol 11:155–162

    Article  PubMed  CAS  Google Scholar 

  • Donnelly A, Blagg BSJ (2008) Novobiocin and additional inhibitors of the Hsp90 C-terminal nucleotide-binding pocket. Curr Med Chem 15:2702–2717

    Article  PubMed  CAS  Google Scholar 

  • Doundoulakis T, Xiang A, Lira R et al (2004) Myxopyronin B analogs as inhibitors of RNA polymerase, synthesis and biological evaluation. Bioorg Med Chem Lett 14:5667–5672

    Article  PubMed  CAS  Google Scholar 

  • Downes CS, Ord MJ, Mullinger AM et al (1985) Novobiocin inhibition of DNA excision repair may occur through effects on mitochondrial structure and ATP metabolism, not on repair topoisomerases. Carcinogenesis 6:1343–1352

    Article  PubMed  CAS  Google Scholar 

  • Floss HG, Yu TW (2005) Rifamycin: mode of action, resistance, and biosynthesis. Chem Rev 105:621–632

    Article  PubMed  CAS  Google Scholar 

  • Foti JJ, Devadoss B, Winkler JA et al (2012) Oxidation of the guanine nucleotide pool underlies cell death by bactericidal antibiotics. Science 336:315–319

    Article  PubMed  CAS  Google Scholar 

  • Gerber M, Ackermann G (2008) OPT-80, a macrocyclic antimicrobial agent for the treatment of Clostridium difficile infections: a review. Expert Opin Investig Drugs 17:547–553

    Article  PubMed  CAS  Google Scholar 

  • Gualtieri M, Tupin A, Brodolin K et al (2009) Frequency and characterisation of spontaneous lipiarmycin-resistant Enterococcus faecalis mutants selected in vitro. Int J Antimicrob Agents 34:605–606

    Article  PubMed  CAS  Google Scholar 

  • Heddle JG, Blance SJ, Zamble DB et al (2001) The antibiotic microcin B17 is a DNA gyrase poison: characterization of the mode of inhibition. J Mol Biol 307:1223–1234

    Article  PubMed  CAS  Google Scholar 

  • Ho M, Hudson B, Das K et al (2009) Structures of RNA polymerase-antibiotic complexes. Curr Opin Structl Biol 19:715–723

    Article  CAS  Google Scholar 

  • Irschik H, Jansen R, Gerth K et al (1985) The sorangicins, novel and powerful inhibitors of eubacterial RNA polymerase isolated from myxobacteria. J Antibiot 40:7–13

    Article  Google Scholar 

  • Keren I, Wu Y, Inocencio J et al (2013) Killing by bactericidal antibiotics does not depend on reactive oxygen species. Science 339:1213–1216

    Article  PubMed  CAS  Google Scholar 

  • Kim HK, Nam JY, Lee EK et al (1999) Actinomycin D as a novel SH2 domain ligand inhibits the Shc/Grb2 interaction in B104-1-1 and SAA cells. FEBS Lett 453:174–178

    Article  PubMed  CAS  Google Scholar 

  • Kohanski MA, Dwyer DJ, Hayete B et al (2007) A common mechanism of cellular death induced by bactericidal antibiotics. Cell 130:797–810

    Article  PubMed  CAS  Google Scholar 

  • Kurabachew M, Lu S, Krastel P et al (2008) Lipiarmycin targets RNA polymerase and has good activity against multidrug-resistant strains of Mycobacterium tuberculosis. J Antimicrob Chemother 62:713–719

    Article  PubMed  CAS  Google Scholar 

  • Kurosawa K, Buim VP, VanEssendelft JL et al (2006) Characterization of Streptomyces MITKK-103, a newly isolated actinomycin X2-producer. Appl Microbiol Biotechnol 72:145–154

    Article  PubMed  CAS  Google Scholar 

  • Lafitte D, Lamour V, Tsvetkov PO et al (2002) DNA gyrase interaction with coumarin-based inhibitors: the role of the hydroxybenzoate isopentenyl moiety and the 5′-methyl group of the noviose. Biochemistry 41:7217–7223

    Article  PubMed  CAS  Google Scholar 

  • Lane WJ, Darst SA (2010) Molecular evolution of multisubunit RNA polymerases: structural analysis. J Mol Biol 395:686–704

    Article  PubMed  CAS  Google Scholar 

  • Lee DJ, Minchin SD, Busby SJW (2012) Activating transcription in bacteria. Ann Rev Microbiol 66:125–152

    Article  CAS  Google Scholar 

  • Lewis RJ, Tsai FTF, Wigley DB (1996) Molecular mechanisms of drug inhibition of DNA gyrase. BioEssays 18:661–671

    Article  PubMed  CAS  Google Scholar 

  • Lira R, Xiang A, Doundoulakis T et al (2007) Syntheses of novel myxopyronin B analogs as potential inhibitors of bacterial RNA polymerase. Bioorg Med Chem Lett 17:6797–6800

    Article  PubMed  CAS  Google Scholar 

  • Liu Y, Imlay JA (2013) Cell death from antibiotics without the involvement of reactive oxygen species. Science 339:1210–1213

    Article  PubMed  CAS  Google Scholar 

  • Mariani R, Maffioli S (2009) Bacterial RNA polymerase inhibitors: an organized overview of their structure, derivatives, biological activity and current clinical development status. Curr Med Chem 16:430–454

    Article  PubMed  CAS  Google Scholar 

  • Mariner K, McPhillie M, Trowbridge R et al (2011) Activity and development of resistance to corallopyronin A, an inhibitor of RNA polymerase. Antimicrob Agents Chemother 55:2413–2416

    Article  PubMed  CAS  Google Scholar 

  • Maxwell A, Lawson DM (2003) The ATP-binding site of type II topoisomerases as a target for antibacterial drugs. Curr Top Med Chem 3:283–303

    Article  PubMed  CAS  Google Scholar 

  • Miller M (2010) Fidaxomicin (OPT-80) for the treatment of Clostridium difficile infection. Expert Opin Pharmacother 11:1569–1578

    Article  PubMed  CAS  Google Scholar 

  • Mukhopadhyay J, Sineva E, Knight J et al (2004) Antibacterial peptide microcin J25 inhibits transcription by binding within and obstructing the RNA polymerase secondary channel. Mol Cell 14:739–751

    Article  PubMed  CAS  Google Scholar 

  • Mukhopadhyay J, Das K, Ismail S et al (2008) The RNA polymerase “switch region” is a target for inhibitors. Cell 135:295–307

    Article  PubMed  CAS  Google Scholar 

  • Oblak M, Kotnik M, Solmajer T (2007) Discovery and development of ATPase inhibitors of DNA gyrase as antibacterial agents. Curr Med Chem 14:2033–2047

    Article  PubMed  CAS  Google Scholar 

  • O’Neill A, Oliva B, Storey C et al (2000) RNA polymerase inhibitors with activity against rifampin-resistant mutants of Staphylococcus aureus. Antimicrobial Agents Chemother 44:3163–3166

    Article  Google Scholar 

  • Panda D, Rathinasamy K, Santra MK et al (2005) Kinetic suppression of microtubule dynamic instability by griseofulvin: implications for its possible use in the treatment of cancer. Proc Natl Acad Sci USA 102:9878–9883

    Article  PubMed  CAS  Google Scholar 

  • Paramanathan T, Vladescu I, McCauley MJ et al (2012) Spectroscopy reveals the DNA structural dynamics that govern the slow binding of Actinomycin D. Nucl Acids Res 40:4925–4932

    Article  PubMed  CAS  Google Scholar 

  • Pommier Y, Leo E, Zhang H et al (2010) DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chem Biol 17:421–433

    Article  PubMed  CAS  Google Scholar 

  • Praveen V, Tripathi CKM (2009) Studies on the production of actinomycin-D by Streptomyces griseoruber—a novel source. Lett Appl Microbiol 49:450–455

    Article  PubMed  CAS  Google Scholar 

  • Pronin SV, Kozmin SA (2010) Synthesis of streptolydigin, a potent bacterial RNA polymerase inhibitor. J Am Chem Soc 132:14394–14396

    Article  PubMed  CAS  Google Scholar 

  • Raab MS, Breitkreutz I, Anderhub S et al (2012) GF-15, a novel inhibitor of centrosomal clustering, suppresses tumor cell growth in vitro and in vivo. Cancer Res 72:5374–5385

    Article  PubMed  CAS  Google Scholar 

  • Rathinasamy K, Jindal B, Asthana J et al (2010) Griseofulvin stabilizes microtubule dynamics, activates p53 and inhibits the proliferation of MCF-7 cells synergistically with vinblastine. BMC Cancer 10:213. doi:10.1186/1471-2407-10-213

    Article  PubMed  Google Scholar 

  • Rebacz B, Larsen TO, Clausen MH et al (2007) Identification of griseofulvin as an inhibitor of centrosomal clustering in a phenotype-based screen. Cancer Res 67:6342–6350

    Article  PubMed  CAS  Google Scholar 

  • Rentsch A, Kalesse M (2012) The total synthesis of corallopyronin A and myxopyronin B. Angew Chem Int Ed Engl 51:11381–11384

    Article  PubMed  CAS  Google Scholar 

  • Richter SN, Menegazzo I, Fabris D et al (2004) Concerted bis-alkylating reactivity of clerocidin towards inpaired cytosine residues in DNA. Nucl Acids Res 32:5658–5667

    Article  PubMed  CAS  Google Scholar 

  • Rosengren K, Clark R, Daly N et al (2003) Microcin J25 has a threaded sidechain-to-backbone ring structure and not a head-to-tail cyclized backbone. J Am Chem Soc 125:12464–12474

    Article  PubMed  CAS  Google Scholar 

  • Saecker R, Record MJ, Dehaseth P (2011) Mechanism of bacterial transcription initiation: RNA polymerase-promoter binding, isomerization to initiation-competent open complexes, and initiation of RNA synthesis. J Mol Biol 412:754–771

    Article  PubMed  CAS  Google Scholar 

  • Saíz-Urra L, Cabrera Pérez MA, Helquera AM et al (2011) Combining molecular docking and QSAR studies for modelling the antigyrase activity of cyclothialidine derivatives. Eur J Med Chem 46:2736–2747

    Article  PubMed  Google Scholar 

  • Schobert R, Schlenk A (2008) Tetramic and tetronic acids: an update on new derivatives and biological aspects. Bioorg Med Chem 16:4203–4221

    Article  PubMed  CAS  Google Scholar 

  • Schröder W, Goerke C, Wolz C (2012) Opposing effects of aminocoumarins and fluoroquinolones on the SOS response and adaptability in Staphylococcus aureus. J Antimicrob Chemother (in press) [Epub ahead of print]

    Google Scholar 

  • Sekine S, Tagami S, Yokoyama S (2012) Structural basis of transcription by bacterial and eukaryotic RNA polymerases. Curr Opin Struct Biol 22:110–118

    Article  PubMed  CAS  Google Scholar 

  • Smith AB, Dong S, Fox RJ et al (2011) Sorangicin A: evolution of a viable synthetic strategy. Tetrahedron 67:9809–9828

    Article  PubMed  CAS  Google Scholar 

  • Solbiati J, Ciaccio M, Farias R et al (1999) Sequence analysis of the four plasmid genes required to produce the circular peptide antibiotic microcin J25. J Bacteriol 181:2659–2662

    PubMed  CAS  Google Scholar 

  • Sousa R (2008) Inhibiting RNA polymerase. Cell 135:205–207

    Article  PubMed  CAS  Google Scholar 

  • Srivastava A, Talaue M, Liu S et al (2011) New target for inhibition of bacterial RNA polymerase: “switch region”. Curr Opin Microbiol 14:532–543

    Article  PubMed  CAS  Google Scholar 

  • Tambo-ong A, Chopra S, Glaser BT et al (2011) Mannich reaction derivatives of novobiocin with modulated physiochemical properties and their antibacterial activities. Bioorg Med Chem Lett 21:5697–5700

    Article  PubMed  CAS  Google Scholar 

  • Temiakov D, Zenkin N, Vassylyeva MN et al (2005) Structural basis of transcription inhibition by antibiotic Streptolydigin. Mol Cell 19:655–666

    Article  PubMed  CAS  Google Scholar 

  • Thompson RE, Jolliffe KA, Payne RJ (2011) Total synthesis of microcin B17 via a fragment condensation approach. Org Lett 13:680–683

    Article  PubMed  CAS  Google Scholar 

  • Tomasz M (1995) Mitomycin C: small, fast and deadly (but very selective). Chem Biol 2:575–579

    Article  PubMed  CAS  Google Scholar 

  • Traynor KK (2011) Fidaxomicin approved for C. difficile infections. Am J Health Syst Pharm 68:1276. doi:10.2146/news110046

    Google Scholar 

  • Tsai FTF, Singh OMP, Skarzynski T et al (1997) The high-resolution crystal structure of a 24-kDa gyrase B fragment from E. coli complexed with one of the most potent coumarin inhibitors, clorobiocin. Proteins 28:41–52

    Article  PubMed  CAS  Google Scholar 

  • Tupin A, Gualtieri M, Brodolin K et al (2009) Myxopyronin: a punch in the jaws of bacterial RNA polymerase. Future Microbiol 4:145–149

    Article  PubMed  CAS  Google Scholar 

  • Tuske S, Sarafianos SG, Wang X et al (2005) Inhibition of bacterial RNA polymerase by streptolydigin: stabilization of a straight-bridge-helix active-center conformation. Cell 122:541–552

    Article  PubMed  CAS  Google Scholar 

  • Venugopal AA, Johnson S (2012) Fidaxomicin: a novel macrocyclic antibiotic approved for treatment of Clostridium difficile infection. Clin Infect Dis 54:568–574

    Article  PubMed  Google Scholar 

  • Villain-Guillot P, Bastide L, Gualtieri M et al (2007) Progress in targeting bacterial transcription. Drug Discov Today 12:200–208

    Article  PubMed  CAS  Google Scholar 

  • Waksman SA (1947) What is an antibiotic or an antibiotic substance? Mycologia 39:565–569

    Article  PubMed  CAS  Google Scholar 

  • Wang ZX, Li SM, Heide L (2000) Identification of the coumermycin A1 biosynthetic gene cluster of Streptomyces rishiriensis DSM 40489. Antimicrob Agents Chemother 44:3040–3048

    Article  PubMed  CAS  Google Scholar 

  • Warren AJ, Hamilton JW (1996) Synthesis and structural characterization of the N2G-mitomycin C-N2G interstrand cross-link in a model synthetic 23 base pair oligonucleotide DNA duplex. Chem Res Toxicol 9:1063–1071

    Article  PubMed  CAS  Google Scholar 

  • Watanabe J, Nakada N, Sawairi S et al (1994) Cyclothialidine, a novel DNA gyrase inhibitor. J Antib. 47:32–36

    Google Scholar 

  • Winter P, Hiller W, Christmann M (2012) Total synthesis of the RNA polymerase inhibitor ripostatin B. Angew Chem Int Ed 51:3396–3400

    Article  CAS  Google Scholar 

  • Wilson K, Kalkum M, Ottesen J et al (2003) Structure of microcin J25, a peptide inhibitor of bacterial RNA polymerase, is a lassoed tail. J Am Chem Soc 125:12475–12483

    Article  PubMed  CAS  Google Scholar 

  • Wolkenberg SE, Boger DL (2002) Mechanisms of in situ activation of DNA targeting antitumor agents. Chem Rev 102:2477–2496

    Article  PubMed  CAS  Google Scholar 

  • Yadav JS, Dhara S, Hossain SS et al (2012) Total synthesis of tirandamycin C utilizing a desymmetrization protocol. J Org Chem 77:9628–9633

    Article  PubMed  CAS  Google Scholar 

  • Yudin AK (ed) (2006) Aziridines and epoxides in organic synthesis. Wiley-VCH, Weinheim

    Google Scholar 

  • Yuzenkova J, Delgado M, Nechaev S et al (2002) Mutations of bacterial RNA polymerase leading to resistance to microcin J25. J Biol Chem 277:50867–50875

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Genetics and Microbiology, University of Murcia, Murcia, Spain

    M. Gacto, M. Madrid, A. Franco, T. Soto, J. Cansado & J. Vicente-Soler

Authors
  1. M. Gacto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Madrid
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. Franco
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T. Soto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J. Cansado
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J. Vicente-Soler
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. Gacto .

Editor information

Editors and Affiliations

  1. Faculty of Pharmacy, Dep Microbiology Parasitology, University of Santiago de Compostela, Santiago de Compostela, Spain

    Tomás G. Villa

  2. Biomedical Center, Lund University, Lund, Sweden

    Patricia Veiga-Crespo

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Gacto, M., Madrid, M., Franco, A., Soto, T., Cansado, J., Vicente-Soler, J. (2014). The Cornerstone of Nucleic Acid-Affecting Antibiotics in Bacteria. In: Villa, T., Veiga-Crespo, P. (eds) Antimicrobial Compounds. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-40444-3_6

Download citation

Publish with us

Policies and ethics

Search

Navigation