Skip to main content
SpringerLink
Log in
Book cover

Bacterial Biofilms pp 85–105Cite as

Innate and Induced Resistance Mechanisms of Bacterial Biofilms

  • Chapter

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 322))

Bacterial biofilms are highly recalcitrant to antibiotic treatment, which holds serious consequences for therapy of infections that involve biofilms. The genetic mechanisms of this biofilm antibiotic resistance appear to fall into two general classes: innate resistance factors and induced resistance factors. Innate mechanisms are activated as part of the biofilm developmental pathway, the factors being integral parts of biofilm structure and physiology. Innate pathways include decreased diffusion of antibiotics through the biofilm matrix, decreased oxygen and nutrient availability accompanied by altered metabolic activity, formation of persisters, and other specific molecules not fitting into the above groups. Induced resistance factors include those resulting from induction by the antimicrobial agent itself. Biofilm antibiotic resistance is likely manifested as an intricate mixture of innate and induced mechanisms. Many researchers are currently trying to overcome this extreme biofilm antibiotic resistance by developing novel therapies aimed at disrupting biofilms and killing the constituent bacteria. These studies have led to the identification of several molecules that effectively disturb biofilm physiology, often by interrupting bacterial quorum sensing. In this manner, manipulation of innate and induced resistance pathways holds much promise for treatment of biofilm infections.

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   169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   219.99
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

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Anderl JN, Franklin MJ, Stewart PS (2000) Role of antibiotic penetration limitation in Klebsiella pneumoniae biofilm resistance to ampicillin and ciprofloxacin. Antimicrob Agents Chemother 44:1818–1824

    Article  PubMed  CAS  Google Scholar 

  • Anderl JN, Zahller J, Roe F, Stewart PS (2003) Role of nutrient limitation and stationary-phase existence in Klebsiella pneumoniae biofilm resistance to ampicillin and ciprofloxacin. Antimicrob Agents Chemother 47:1251–1256

    Article  PubMed  CAS  Google Scholar 

  • Bagge N, Hentzer M, Andersen JB, Ciofu O, Givskov M, Hoiby N (2004a) Dynamics and spatial distribution of beta-lactamase expression in Pseudomonas aeruginosa biofilms. Antimicrob Agents Chemother 48:1168–1174

    Article  PubMed  CAS  Google Scholar 

  • Bagge N, Schuster M, Hentzer M, Ciofu O, Givskov M, Greenberg EP, Hoiby N (2004b) Pseudomonas aeruginosa biofilms exposed to imipenem exhibit changes in global gene expression and beta-lactamase and alginate production. Antimicrob Agents Chemother 48:1175–1187

    Article  PubMed  CAS  Google Scholar 

  • Balaban N, Giacometti A, Cirioni O, Gov Y, Ghiselli R, Mocchegiani F, Viticchi C, Del Prete MS, Saba V, Scalise G, Dell’Acqua G (2003a) Use of the quorum-sensing inhibitor RNAIII-inhibiting peptide to prevent biofilm formation in vivo by drug-resistant Staphylococcus epidermidis. J Infect Dis 187:625–630

    Article  PubMed  CAS  Google Scholar 

  • Balaban N, Gov Y, Bitler A, Boelaert JR (2003b) Prevention of Staphylococcus aureus biofilm on dialysis catheters and adherence to human cells. Kidney Int 63:340–345

    Article  PubMed  Google Scholar 

  • Balaban NQ, Merrin J, Chait R, Kowalik L, Leibler S (2004) Bacterial persistence as a phenotypic switch. Science 305:1622–1625

    Article  PubMed  CAS  Google Scholar 

  • Borriello G, Werner E, Roe F, Kim AM, Ehrlich GD, Stewart PS (2004) Oxygen limitation contributes to antibiotic tolerance of Pseudomonas aeruginosa in biofilms. Antimicrob Agents Chemother 48:2659–2664

    Article  PubMed  CAS  Google Scholar 

  • Borriello G, Richards L, Ehrlich GD, Stewart PS (2006) Arginine or nitrate enhances antibiotic susceptibility of Pseudomonas aeruginosa in biofilms. Antimicrob Agents Chemother 50:382–384

    Article  PubMed  CAS  Google Scholar 

  • Brooun A, Liu S, Lewis K (2000) A dose-response study of antibiotic resistance in Pseudomonas aeruginosa biofilms. Antimicrob Agents Chemother 44:640–646

    Article  PubMed  CAS  Google Scholar 

  • Brown MR, Allison DG, Gilbert P (1988) Resistance of bacterial biofilms to antibiotics: a growth-rate related effect? J Antimicrob Chemother 22:777–780

    Article  PubMed  CAS  Google Scholar 

  • Campanac C, Pineau L, Payard A, Baziard-Mouysset G, Roques C (2002) Interactions between biocide cationic agents and bacterial biofilms. Antimicrob Agents Chemother 46:1469–1474

    Article  PubMed  CAS  Google Scholar 

  • Chan C, Burrows LL, Deber CM (2005) Alginate as an auxiliary bacterial membrane: binding of membrane-active peptides by polysaccharides. J Pept Res 65:343–351

    Article  PubMed  CAS  Google Scholar 

  • Chernish RN, Aaron SD (2003) Approach to resistant Gram-negative bacterial pulmonary infections in patients with cystic fibrosis. Curr Opin Pulm Med 9:509–515

    Article  PubMed  Google Scholar 

  • Costerton JW, Stewart PS, Greenberg EP (1999) Bacterial biofilms: a common cause of persistent infections. Science 284:1318–1322

    Article  PubMed  CAS  Google Scholar 

  • Donaldson SH, Bennett WD, Zeman KL, Knowles MR, Tarran R, Boucher RC (2006) Mucus clearance and lung function in cystic fibrosis with hypertonic saline. N Engl J Med 354:241–250

    Article  PubMed  CAS  Google Scholar 

  • Donlan RM, Costerton JW (2002) Biofilms: survival mechanisms of clinically relevant microorganisms. Clin Microbiol Rev 15:167–193

    Article  PubMed  CAS  Google Scholar 

  • Dunne WM Jr (2002) Bacterial adhesion: seen any good biofilms lately? Clin Microbiol Rev 15:155–166

    Article  PubMed  CAS  Google Scholar 

  • Elkins JG, Hassett DJ, Stewart PS, Schweizer HP, McDermott TR (1999) Protective role of catalase in Pseudomonas aeruginosa biofilm resistance to hydrogen peroxide. Appl Environ Microbiol 65:4594–4600

    PubMed  CAS  Google Scholar 

  • Elkins MR, Robinson M, Rose BR, Harbour C, Moriarty CP, Marks GB, Belousova EG, Xuan W, Bye PT (2006) A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis. N Engl J Med 354:229–240

    Article  PubMed  CAS  Google Scholar 

  • Field TR, White A, Elborn JS, Tunney MM (2005) Effect of oxygen limitation on the in vitro antimicrobial susceptibility of clinical isolates of Pseudomonas aeruginosa grown planktonically and as biofilms. Eur J Clin Microbiol Infect Dis 24:677–687

    Article  PubMed  CAS  Google Scholar 

  • Gibson RL, Burns JL, Ramsey BW (2003) Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med 168:918–951

    Article  PubMed  Google Scholar 

  • Gillis RJ, White KG, Choi KH, Wagner VE, Schweizer HP, Iglewski BH (2005) Molecular basis of azithromycin-resistant Pseudomonas aeruginosa biofilms. Antimicrob Agents Chemother 49:3858–3867

    Article  PubMed  CAS  Google Scholar 

  • Harrison JJ, Ceri H, Roper NJ, Badry EA, Sproule KM, Turner RJ (2005) Persister cells mediate tolerance to metal oxyanions in Escherichia coli. Microbiology 151:3181–3195

    Article  PubMed  CAS  Google Scholar 

  • Hassett DJ, Cuppoletti J, Trapnell B, Lymar SV, Rowe JJ, Yoon SS, Hilliard GM, Parvatiyar K, Kamani MC, Wozniak DJ, Hwang SH, McDermott TR, Ochsner UA (2002) Anaerobic metabolism and quorum sensing by Pseudomonas aeruginosa biofilms in chronically infected cystic fibrosis airways: rethinking antibiotic treatment strategies and drug targets. Adv Drug Deliv Rev 54:1425–1443

    Article  PubMed  CAS  Google Scholar 

  • Hentzer M, Riedel K, Rasmussen TB, Heydorn A, Andersen JB, Parsek MR, Rice SA, Eberl L, Molin S, Hoiby N, Kjelleberg S, Givskov M (2002) Inhibition of quorum sensing in Pseudomonas aeruginosa biofilm bacteria by a halogenated furanone compound. Microbiology 148:87–102

    PubMed  CAS  Google Scholar 

  • Hoffman LR, D’Argenio DA, MacCoss MJ, Zhang Z, Jones RA, Miller SI (2005) Aminoglycoside antibiotics induce bacterial biofilm formation. Nature 436:1171–1175

    Article  PubMed  CAS  Google Scholar 

  • Hoiby N, Frederiksen B, Pressler T (2005) Eradication of early Pseudomonas aeruginosa infection. J Cyst Fibros 4 [Suppl 2]:49–54

    Article  PubMed  CAS  Google Scholar 

  • Jabra-Rizk MA, Meiller TF, James CE, Shirtliff ME (2006) Effect of farnesol on Staphylococcus aureus biofilm formation and antimicrobial susceptibility. Antimicrob Agents Chemother 50:1463–1469

    Article  PubMed  CAS  Google Scholar 

  • Kaldalu N, Mei R, Lewis K (2004) Killing by ampicillin and ofloxacin induces overlapping changes in Escherichia coli transcription profile. Antimicrob Agents Chemother 48:890–896

    Article  PubMed  CAS  Google Scholar 

  • Kaplan D, Christiaen D, Arad SM (1987) Chelating properties of extracellular polysaccharides from Chlorella spp. Appl Environ Microbiol 53:2953–2956

    PubMed  CAS  Google Scholar 

  • Keren I, Kaldalu N, Spoering A, Wang Y, Lewis K (2004a) Persister cells and tolerance to antimicrobials. FEMS Microbiol Lett 230:13–18

    Article  PubMed  CAS  Google Scholar 

  • Keren I, Shah D, Spoering A, Kaldalu N, Lewis K (2004b) Specialized persister cells and the mechanism of multidrug tolerance in Escherichia coli. J Bacteriol 186:8172–8180

    Article  PubMed  CAS  Google Scholar 

  • Kunduru MR, Pometto AL 3rd (1996) Continuous ethanol production by Zymomonas mobilis and Saccharomyces cerevisiae in biofilm reactors. J Ind Microbiol 16:249–256

    Article  PubMed  CAS  Google Scholar 

  • Lendenmann U, Spain JC, Smets BF (1998) Simultaneous biodegradation of 2, 4-dinitrotoluene and 2, 6-dinitrotoluene in an aerobic fluidized-bed biofilm reactor. Environ Sci Technol 32:82–87

    Article  CAS  Google Scholar 

  • Lewis K (2005) Persister cells and the riddle of biofilm survival. Biochemistry (Mosc) 70:267–274

    Article  CAS  Google Scholar 

  • Li XZ, Webb JS, Kjelleberg S, Rosche B (2006) Enhanced benzaldehyde tolerance in Zymomonas mobilis biofilms and the potential of biofilm applications in fine-chemical production. Appl Environ Microbiol 72:1639–1644

    Article  PubMed  CAS  Google Scholar 

  • Luke AK, Burton SG (2001) A novel application for Neurospora crassa: Progress from batch culture to a membrane bioreactor for the bioremediation of phenols. Enzyme Microb Technol 29:348–356

    Article  CAS  Google Scholar 

  • Mah TF, O’Toole GA (2001) Mechanisms of biofilm resistance to antimicrobial agents. Trends Microbiol 9:34–39

    Article  PubMed  CAS  Google Scholar 

  • Mah TF, Pitts B, Pellock B, Walker GC, Stewart PS, O’Toole GA (2003) A genetic basis for Pseudomonas aeruginosa biofilm antibiotic resistance. Nature 426:306–310

    Article  PubMed  CAS  Google Scholar 

  • Manefield M, Harris L, Rice SA, de Nys R, Kjelleberg S (2000) Inhibition of luminescence and virulence in the black tiger prawn (Penaeus monodon) pathogen Vibrio harveyi by intercellular signal antagonists. Appl Environ Microbiol 66:2079–2084

    Article  PubMed  CAS  Google Scholar 

  • McLean RJ, Beauchemin D, Clapham L, Beveridge TJ (1990) Metal-binding characteristics of the gamma-glutamyl capsular polymer of Bacillus licheniformis ATCC 9945. Appl Environ Microbiol 56:3671–3677

    PubMed  CAS  Google Scholar 

  • Mittelman MW, Geesey GG (1985) Copper-binding characteristics of exopolymers from a freshwater-sediment bacterium. Appl Environ Microbiol 49:846–851

    PubMed  CAS  Google Scholar 

  • Morikawa M (2006) Beneficial biofilm formation by industrial bacteria Bacillus subtilis and related species. J Biosci Bioeng 101:1–8

    Article  PubMed  CAS  Google Scholar 

  • Moyed HS, Bertrand KP (1983) hipA, a newly recognized gene of Escherichia coli K-12 that affects frequency of persistence after inhibition of murein synthesis. J Bacteriol 155:768–775

    PubMed  CAS  Google Scholar 

  • Nichols WW, Dorrington SM, Slack MP, Walmsley HL (1988) Inhibition of tobramycin diffusion by binding to alginate. Antimicrob Agents Chemother 32:518–523

    PubMed  CAS  Google Scholar 

  • Nicolella C, van Loosdrecht MC, Heijnen JJ (2000) Wastewater treatment with particulate biofilm reactors. J Biotechnol 80:1–33

    Article  PubMed  CAS  Google Scholar 

  • Pages JM, Masi M, Barbe J (2005) Inhibitors of efflux pumps in Gram-negative bacteria. Trends Mol Med 11:382–389

    Article  PubMed  CAS  Google Scholar 

  • Patel R (2005) Biofilms and antimicrobial resistance. Clin Orthop Relat Res:41–47

    Google Scholar 

  • Pedersen K, Christensen SK, Gerdes K (2002) Rapid induction and reversal of a bacteriostatic condition by controlled expression of toxins and antitoxins. Mol Microbiol 45:501–510

    Article  PubMed  CAS  Google Scholar 

  • Rachid S, Ohlsen K, Witte W, Hacker J, Ziebuhr W (2000) Effect of subinhibitory antibiotic concentrations on polysaccharide intercellular adhesin expression in biofilm-forming Staphylococcus epidermidis. Antimicrob Agents Chemother 44:3357–3363

    Article  PubMed  CAS  Google Scholar 

  • Rasmussen TB, Manefield M, Andersen JB, Eberl L, Anthoni U, Christophersen C, Steinberg P, Kjelleberg S, Givskov M (2000) How Delisea pulchra furanones affect quorum sensing and swarming motility in Serratia liquefaciens MG1. Microbiology 146:3237–3244

    PubMed  CAS  Google Scholar 

  • Rasmussen TB, Skindersoe ME, Bjarnsholt T, Phipps RK, Christensen KB, Jensen PO, Andersen JB, Koch B, Larsen TO, Hentzer M, Eberl L, Hoiby N, Givskov M (2005) Identity and effects of quorum-sensing inhibitors produced by Penicillium species. Microbiology 151:1325–1340

    Article  PubMed  CAS  Google Scholar 

  • Rasmussen TB, Givskov M (2006) Quorum-sensing inhibitors as anti-pathogenic drugs. Int J Med Microbiol 296:149–161

    Article  PubMed  CAS  Google Scholar 

  • Ren D, Sims JJ, Wood TK (2002) Inhibition of biofilm formation and swarming of Bacillus subtilis by (5Z)-4-bromo-5-(bromomethylene)-3-butyl-2(5H)-furanone. Lett Appl Microbiol 34:293–299

    Article  PubMed  CAS  Google Scholar 

  • Ren D, Bedzyk LA, Setlow P, England DF, Kjelleberg S, Thomas SM, Ye RW, Wood TK (2004) Differential gene expression to investigate the effect of (5Z)-4-bromo- 5-(bromomethylene)-3-butyl-2(5H)-furanone on Bacillus subtilis. Appl Environ Microbiol 70:4941–4949

    Article  PubMed  CAS  Google Scholar 

  • Ren D, Zuo R, Gonzalez Barrios AF, Bedzyk LA, Eldridge GR, Pasmore ME, Wood TK (2005) Differential gene expression for investigation of Escherichia coli biofilm inhibition by plant extract ursolic acid. Appl Environ Microbiol 71:4022–4034

    Article  PubMed  CAS  Google Scholar 

  • Roberts ME, Stewart PS (2005) Modelling protection from antimicrobial agents in biofilms through the formation of persister cells. Microbiology 151:75–80

    Article  PubMed  CAS  Google Scholar 

  • Sailer FC, Meberg BM, Young KD (2003) beta-Lactam induction of colanic acid gene expression in Escherichia coli. FEMS Microbiol Lett 226:245–249

    Article  PubMed  CAS  Google Scholar 

  • Schembri MA, Kjaergaard K, Klemm P (2003) Global gene expression in Escherichia coli biofilms. Mol Microbiol 48:253–267

    Article  PubMed  CAS  Google Scholar 

  • Ren D, Bedzyk LA, Setlow P, England DF, Kjelleberg S, Thomas SM, Ye RW, Wood TK (2004) Differential gene expression to investigate the effect of (5Z)-4-bromo- 5-(bromomethylene)-3- butyl-2(5H)-furanone on Bacillus subtilis. Appl Environ Microbiol 70:4941–4949

    Article  PubMed  CAS  Google Scholar 

  • Ren D, Zuo R, Gonzalez Barrios AF, Bedzyk LA, Eldridge GR, Pasmore ME, Wood TK (2005) Differential gene expression for investigation of Escherichia coli biofilm inhibition by plant extract ursolic acid. Appl Environ Microbiol 71:4022–4034

    Article  PubMed  CAS  Google Scholar 

  • Roberts ME, Stewart PS (2005) Modelling protection from antimicrobial agents in biofilms through the formation of persister cells. Microbiology 151:75–80

    Article  PubMed  CAS  Google Scholar 

  • Sailer FC, Meberg BM, Young KD (2003) beta-Lactam induction of colanic acid gene expression in Escherichia coli. FEMS Microbiol Lett 226:245-249

    Article  PubMed  CAS  Google Scholar 

  • Schembri MA, Kjaergaard K, Klemm P (2003) Global gene expression in Escherichia coli biofilms. Mol Microbiol 48:253–267

    Article  PubMed  CAS  Google Scholar 

  • Shah D, Zhang Z, Khodursky A, Kaldalu N, Kurg K, Lewis K (2006) Persisters: a distinct physiological state of E. coli. BMC Microbiol 6:53–61

    Article  PubMed  Google Scholar 

  • Singh P, Cameotra SS (2004) Enhancement of metal bioremediation by use of microbial surfactants. Biochem Biophys Res Commun 319:291–297

    Article  PubMed  CAS  Google Scholar 

  • Smith AW (2005) Biofilms and antibiotic therapy: is there a role for combating bacterial resistance by the use of novel drug delivery systems? Adv Drug Deliv Rev 57:1539–1550

    Article  PubMed  CAS  Google Scholar 

  • Spoering AL, Lewis K (2001) Biofilms and planktonic cells of Pseudomonas aeruginosa have similar resistance to killing by antimicrobials. J Bacteriol 183:6746–6751

    Article  PubMed  CAS  Google Scholar 

  • Spoering AL, Vulic M, Lewis K (2006) GlpD and PlsB participate in persister cell formation in Escherichia coli. J Bacteriol 188:5136–5144

    Article  PubMed  CAS  Google Scholar 

  • Steinberg PD, Schneider R, Kjelleberg S (1997) Chemical defenses of seaweeds against microbial colonization. Biodegradation 8:211–220

    Article  CAS  Google Scholar 

  • Stewart PS, Costerton JW (2001) Antibiotic resistance of bacteria in biofilms. Lancet 358:135–138

    Article  PubMed  CAS  Google Scholar 

  • Stone G, Wood P, Dixon L, Keyhan M, Matin A (2002) Tetracycline rapidly reaches all the constituent cells of uropathogenic Escherichia coli biofilms. Antimicrob Agents Chemother 46:2458–2461

    Article  PubMed  CAS  Google Scholar 

  • Szomolay B, Klapper I, Dockery J, Stewart PS (2005) Adaptive responses to antimicrobial agents in biofilms. Environ Microbiol 7:1186–1191

    Article  PubMed  CAS  Google Scholar 

  • Teitzel GM, Parsek MR (2003) Heavy metal resistance of biofilm and planktonic Pseudomonas aeruginosa. Appl Environ Microbiol 69:2313–2320

    Article  PubMed  CAS  Google Scholar 

  • Walters MC 3rd, Roe F, Bugnicourt A, Franklin MJ, Stewart PS (2003) Contributions of antibiotic penetration, oxygen limitation, and low metabolic activity to tolerance of Pseudomonas aeruginosa biofilms to ciprofloxacin and tobramycin. Antimicrob Agents Chemother 47:317–323

    Article  PubMed  CAS  Google Scholar 

  • Whiteley M, Bangera MG, Bumgarner RE, Parsek MR, Teitzel GM, Lory S, Greenberg EP (2001) Gene expression in Pseudomonas aeruginosa biofilms. Nature 413:860–864

    Article  PubMed  CAS  Google Scholar 

  • Wozniak DJ, Keyser R (2004) Effects of subinhibitory concentrations of macrolide antibiotics on Pseudomonas aeruginosa. Chest 125:62S–69S; quiz 69S

    Article  PubMed  CAS  Google Scholar 

  • Xu KD, Stewart PS, Xia F, Huang CT, McFeters GA (1998) Spatial physiological heterogeneity in Pseudomonas aeruginosa biofilm is determined by oxygen availability. Appl Environ Microbiol 64:4035–4039

    PubMed  CAS  Google Scholar 

  • Zahller J, Stewart PS (2002) Transmission electron microscopic study of antibiotic action on Klebsiella pneumoniae biofilm. Antimicrob Agents Chemother 46:2679–2683

    Article  PubMed  CAS  Google Scholar 

  • Zhang S, Norrlow O, Wawrzynczyk J, Dey ES (2004) Poly(3-hydroxybutyrate) biosynthesis in the biofilm of Alcaligenes eutrophus, using glucose enzymatically released from pulp fiber sludge. Appl Environ Microbiol 70:6776–6782

    Article  PubMed  CAS  Google Scholar 

  • Zheng Z, Stewart PS (2002) Penetration of rifampin through Staphylococcus epidermidis biofilms. Antimicrob Agents Chemother 46:900–903

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Microbiology and Immunology, Dartmouth Medical School, 03755, Hanover, NH, USA

    G. G. Anderson & G. A. O'Toole

Authors
  1. G. G. Anderson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G. A. O'Toole
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Emory University School of Medicine, 1510 Clifton Rd, 30322, Atlanta, GA, USA

    Tony Romeo

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Anderson, G.G., O'Toole, G.A. (2008). Innate and Induced Resistance Mechanisms of Bacterial Biofilms. In: Romeo, T. (eds) Bacterial Biofilms. Current Topics in Microbiology and Immunology, vol 322. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-75418-3_5

Download citation

Publish with us

Policies and ethics

Search

Navigation