Phage “delay” towards enhancing bacterial escape from biofilms: a more comprehensive way of viewing resistance to bacteriophages

Stephen T. Abedon; Stephen T. Abedon

doi:10.3934/microbiol.2017.2.186

AIMS Microbiology

2017, Volume 3, Issue 2: 186-226. doi: 10.3934/microbiol.2017.2.186

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Opinion paper

Phage “delay” towards enhancing bacterial escape from biofilms: a more comprehensive way of viewing resistance to bacteriophages

Stephen T. Abedon ^,

Department of Microbiology, the Ohio State University, 1680 University Dr., Mansfield, OH 44906, USA

Received: 15 January 2017 Accepted: 17 March 2017 Published: 31 March 2017

In exploring bacterial resistance to bacteriophages, emphasis typically is placed on those mechanisms which completely prevent phage replication. Such resistance can be detected as extensive reductions in phage ability to form plaques, that is, reduced efficiency of plating. Mechanisms include restriction-modification systems, CRISPR/Cas systems, and abortive infection systems. Alternatively, phages may be reduced in their “vigor” when infecting certain bacterial hosts, that is, with phages displaying smaller burst sizes or extended latent periods rather than being outright inactivated. It is well known, as well, that most phages poorly infect bacteria that are less metabolically active. Extracellular polymers such as biofilm matrix material also may at least slow phage penetration to bacterial surfaces. Here I suggest that such “less-robust” mechanisms of resistance to bacteriophages could serve bacteria by slowing phage propagation within bacterial biofilms, that is, delaying phage impact on multiple bacteria rather than necessarily outright preventing such impact. Related bacteria, ones that are relatively near to infected bacteria, e.g., roughly 10+ µm away, consequently may be able to escape from biofilms with greater likelihood via standard dissemination-initiating mechanisms including erosion from biofilm surfaces or seeding dispersal/central hollowing. That is, given localized areas of phage infection, so long as phage spread can be reduced in rate from initial points of contact with susceptible bacteria, then bacterial survival may be enhanced due to bacteria metaphorically “running away” to more phage-free locations. Delay mechanisms—to the extent that they are less specific in terms of what phages are targeted—collectively could represent broader bacterial strategies of phage resistance versus outright phage killing, the latter especially as require specific, evolved molecular recognition of phage presence. The potential for phage delay should be taken into account when developing protocols of phage-mediated biocontrol of biofilm bacteria, e.g., as during phage therapy of chronic bacterial infections.
- abortive infection systems,
- bacteriophage therapy,
- biofilm,
- central hollowing,
- native dispersion,
- dissemination,
- extracellular polymeric substances,
- microcolony,
- phage resistance,
- phage therapy,
- reduced infection vigor,
- seeding dispersal
Citation: Stephen T. Abedon. Phage “delay” towards enhancing bacterial escape from biofilms: a more comprehensive way of viewing resistance to bacteriophages[J]. AIMS Microbiology, 2017, 3(2): 186-226. doi: 10.3934/microbiol.2017.2.186

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Abstract

In exploring bacterial resistance to bacteriophages, emphasis typically is placed on those mechanisms which completely prevent phage replication. Such resistance can be detected as extensive reductions in phage ability to form plaques, that is, reduced efficiency of plating. Mechanisms include restriction-modification systems, CRISPR/Cas systems, and abortive infection systems. Alternatively, phages may be reduced in their “vigor” when infecting certain bacterial hosts, that is, with phages displaying smaller burst sizes or extended latent periods rather than being outright inactivated. It is well known, as well, that most phages poorly infect bacteria that are less metabolically active. Extracellular polymers such as biofilm matrix material also may at least slow phage penetration to bacterial surfaces. Here I suggest that such “less-robust” mechanisms of resistance to bacteriophages could serve bacteria by slowing phage propagation within bacterial biofilms, that is, delaying phage impact on multiple bacteria rather than necessarily outright preventing such impact. Related bacteria, ones that are relatively near to infected bacteria, e.g., roughly 10+ µm away, consequently may be able to escape from biofilms with greater likelihood via standard dissemination-initiating mechanisms including erosion from biofilm surfaces or seeding dispersal/central hollowing. That is, given localized areas of phage infection, so long as phage spread can be reduced in rate from initial points of contact with susceptible bacteria, then bacterial survival may be enhanced due to bacteria metaphorically “running away” to more phage-free locations. Delay mechanisms—to the extent that they are less specific in terms of what phages are targeted—collectively could represent broader bacterial strategies of phage resistance versus outright phage killing, the latter especially as require specific, evolved molecular recognition of phage presence. The potential for phage delay should be taken into account when developing protocols of phage-mediated biocontrol of biofilm bacteria, e.g., as during phage therapy of chronic bacterial infections.

References

[1]	Whitman WB, Coleman DC, Wiebe WJ (1998) Prokaryotes: The unseen majority. Proc Natl Acad Sci USA 95: 6578–6583.
[2]	Flemming HC, Wingender J (2010) The biofilm matrix. Nat Rev Microbiol 8: 623–633.
[3]	Hall MR, McGillicuddy E, Kaplan LJ (2014) Biofilm: basic principles, pathophysiology, and implications for clinicians. Surg Infect (Larchmt ) 15: 1–7.
[4]	Hyman P, Abedon ST (2012) Smaller fleas: viruses of microorganisms. Scientifica 2012: 734023.
[5]	Wommack KE, Colwell RR (2000) Virioplankton: viruses in aquatic ecosystems. Microbiol Mol Biol Rev 64: 69–114.
[6]	Weinbauer MG (2004) Ecology of prokaryotic viruses. FEMS Microbiol Rev 28: 127–181.
[7]	Abedon ST (2015) Ecology of anti-biofilm agents I. antibiotics versus bacteriophages. Pharmaceuticals 8: 525–558.
[8]	Abedon ST (2015) Ecology of anti-biofilm agents II. bacteriophage exploitation and biocontrol of biofilm bacteria. Pharmaceuticals 8: 559–589.
[9]	Briandet R, Lacroix-Gueu P, Renault M, et al. (2008) Fluorescence correlation spectroscopy to study diffusion and reaction of bacteriophages inside biofilms. Appl Environ Microbiol 74: 2135–2143.
[10]	Fukuyo M, Sasaki A, Kobayashi I (2012) Success of a suicidal defense strategy against infection in a structured habitat. Sci Rep 2: 238.
[11]	Hyman P, Abedon ST (2010) Bacteriophage host range and bacterial resistance. Adv Appl Microbiol 70: 217–248.
[12]	Labrie SJ, Samson JE, Moineau S (2010) Bacteriophage resistance mechanisms. Nat Rev Microbiol 8: 317–327.
[13]	Dy RL, Richter C, Salmond GP, et al. (2014) Remarkable mechanisms in microbes to resist phage infections. Annu Rev Virol 1: 307–331.
[14]	Seed KD (2015) Battling phages: How bacteria defend against viral attack. PLoS Path 11: e1004847.
[15]	Parma DH, Snyder M, Sobolevski S, et al. (1992) The rex system of bacteriophage l: tolerance and altruistic cell death. Genes Dev 6: 497–510.
[16]	Shub DS (1994) Bacterial viruses. Bacterial altruism? Curr Biol 4: 555–556.
[17]	Dy RL, Przybilski R, Semeijn K, et al. (2014) A widespread bacteriophage abortive infection system functions through a Type IV toxin-antitoxin mechanism. Nucl Acids Res 42: 4590–4605.
[18]	Iranzo J, Lobkovsky AE, Wolf YI, et al. (2015) Immunity, suicide or both? Ecological determinants for the combined evolution of anti-pathogen defense systems. BMC Evol Biol 15: 43.
[19]	Dennehy JJ, Abedon ST, Turner PE (2007) Host density impacts relative fitness of bacteriophage f6 genotypes in structured habitats. Evolution 61: 2516–2527.
[20]	Abedon ST, Yin J (2008) Impact of spatial structure on phage population growth, In: Abedon, S.T. Editor, Bacteriophage Ecology, Cambridge, UK: Cambridge University Press, 94–113.
[21]	Abedon ST (2011) Bacteriophages and biofilms: ecology, phage therapy, plaques, Hauppauge, New York: Nova Science Publishers.
[22]	Abedon ST (2016) Bacteriophage exploitation of bacterial biofilms: phage preference for less mature targets? FEMS Microbiol Lett 363: fnv246.
[23]	Abedon ST (2012) Spatial vulnerability: bacterial arrangements, microcolonies, and biofilms as responses to low rather than high phage densities. Viruses 4: 663–687.
[24]	Abedon ST (2012) Thinking about microcolonies as phage targets. Bacteriophage 2: 200–204.
[25]	Abedon ST (2008) Phage population growth: constraints, games, adaptation, In: Abedon, S.T. Editor, Bacteriophage Ecology, Cambridge, UK: Cambridge University Press, 64–93.
[26]	Abedon ST (2009) Impact of phage properties on bacterial survival, In: Adams, H.T. Editor, Contemporary Trends in Bacteriophage Research, Hauppauge, New York: Nova Science Publishers, 217–235.
[27]	Payne RJH, Jansen VAA (2001) Understanding bacteriophage therapy as a density-dependent kinetic process. J Theor Biol 208: 37–48.
[28]	Abedon ST, Thomas-Abedon C (2010) Phage therapy pharmacology. Curr Pharm Biotechnol 11: 28–47.
[29]	Hamilton WD (1964) The genetical evolution of social behaviour. I. J Theor Biol 7: 1–16.
[30]	West SA, Gardner A (2010) Altruism, spite, and greenbeards. Science 327: 1341–1344.
[31]	Iranzo J, Lobkovsky AE, Wolf YI, et al. (2014) Virus-host arms race at the joint origin of multicellularity and programmed cell death. Cell Cycle 13: 3083–3088.
[32]	West SA, Griffin AS, Gardner A, et al. (2006) Social evolution theory for microorganisms. Nat Rev Microbiol 4: 597–607.
[33]	Ewald PW (1994) Evolution of Infectious Disease, New York: Oxford University Press.
[34]	Michod RE, Nedelcu AM, Roze D (2003) Cooperation and conflict in the evolution of individuality. IV. Conflict mediation and evolvability in Volvox carteri. Bio Systems 69: 95–114.
[35]	van Gestel J, Vlamakis H, Kolter R (2015) Division of labor in biofilms: the ecology of cell differentiation. Microbiol Spectr 3: MB-0002-2014.
[36]	Andrews JH (1998) Bacteria as modular organisms. Ann Rev Microbiol 52: 105–126.
[37]	Kaplan JB (2010) Biofilm dispersal: mechanisms, clinical implications, and potential therapeutic uses. J Dent Res 89: 205–218.
[38]	McDougald D, Rice SA, Barraud N, et al. (2012) Should we stay or should we go: mechanisms and ecological consequences for biofilm dispersal. Nat Rev Microbiol 10: 39–50.
[39]	Davies DG (2011) Biofilm disperson, In: Flemming, H.C., Wingender, J., Szewzyk, U. Editors, Biofilm Highlights, Berlin: Springer, 1–28.
[40]	Barraud N, Kjelleberg S, Rice SA (2015) Dispersal from microbial biofilms. Microbiol Spectr 3: MB-0015-2014.
[41]	Petrova OE, Sauer K (2016) Escaping the biofilm in more than one way: desorption, detachment or dispersion. Curr Opin Microbiol 30: 67–78.
[42]	Kim SK, Lee JH (2016) Biofilm dispersion in Pseudomonas aeruginosa. J Microbiol 54: 71–85.
[43]	Ronce O (2007) How does it feel to be like a rolling stone? Ten questions about dispersal evolution. Ann Rev Ecol Evol Syst 38: 231–253.
[44]	Korber DR, Lawrence JR, Lappin-Scott HM, et al. (1995) Growth of microorganisms on surfaces, In: Costerton, J.W., Lappin-Scott, H. Editors, Microbial biofilms, Cambridge, UK: Cambridge University Press, 15–45.
[45]	Bjarnsholt T (2013) The role of bacterial biofilms in chronic infections. Apmis 121: 1–51.
[46]	Battin TJ, Besemer K, Bengtsson MM, et al. (2016) The ecology and biogeochemistry of stream biofilms. Nat Rev Microbiol 14: 251–263.
[47]	Costerton JW, Lappin-Scott H (1995) Introduction to microbial biofilms, In: Costerton, J.W., Lappin-Scott, H. Editors, Microbial biofilms, Cambridge, UK: Cambridge University Press, 1–11.
[48]	Costerton JW, Marrie TJ, Cheng KJ (1985) Phenomena of bacterial adhesion, In: Savage, D.C., Fletcher, M. Editors, Bacterial Adhesion: Mechanisms and Physiological Significance, New York: Plenum Press, 3–43.
[49]	Somerville DA, Noble WC (1973) Microcolony size of microbes on human skin. J Med Microbiol 6: 323–328.
[50]	Mitarai N, Brown S, Sneppen K (2016) Population dynamics of phage and bacteria in spatially structured habitats using phage l and Escherichia coli. J Bacteriol 198: 1783–1793.
[51]	Kreft JU (2004) Biofilms promote altruism. Microbiology 150: 2751–2760.
[52]	Nadell CD, Bassler BL (2011) A fitness trade-off between local competition and dispersal in Vibrio cholerae biofilms. Proc Natl Acad Sci USA 108: 14181–14185.
[53]	Bryers JD (1988) Modeling biofilm accumulation, In: Brazin, M.J., Prosser, J.I. Editors, Physiological Models in Microbiology, Eds., FL: CRC Press, 109–144.
[54]	Garny K, Horn H, Neu TR (2008) Interaction between biofilm development, structure and detachment in rotating annular reactors. Bioprocess Biosyst Eng 31: 619–629.
[55]	Brading MG, Jass J, Lappin-Scott HM (1995) Dynamics of bacterial biofilm formation, In: Costerton, J.W., Lappin-Scott, H. Editors, Microbial biofilms, Cambridge, UK: Cambridge University Press, 46–63.
[56]	Vanysacker L, Boerjan B, Declerck P, et al. (2014) Biofouling ecology as a means to better understand membrane biofouling. Appl Microbiol Biotechnol 98: 8047–8072.
[57]	Bester E, Wolfaardt G, Joubert L, et al. (2005) Planktonic-cell yield of a pseudomonad biofilm. Appl Environ Microbiol 71: 7792–7798.
[58]	Knowles B, Silveira CB, Bailey BA, et al. (2016) Lytic to temperate switching of viral communities. Nature 531: 466–470.
[59]	Gonzalez S, Fernandez L, Campelo AB, et al. (2017) The behavior of Staphylococcus aureus dual-species biofilms treated with bacteriophage phiIPLA-RODI depends on the accompanying microorganism. Appl Environ Microbiol 83: AEM-02821-16.
[60]	Sutherland IW, Hughes KA, Skillman LC, et al. (2004) The interaction of phage and biofilms. FEMS Microbiol Lett 232: 1–6.
[61]	Nale JY, Chutia M, Carr P, et al. (2016) "Get in early"; biofilm and wax moth (Galleria mellonella) models reveal new insights into the therapeutic potential of Clostridium difficile bacteriophages. Front Microbiol 7: 1383.
[62]	Doolittle MM, Cooney JJ, Caldwell DE (1996) Tracing the interaction of bacteriophage with bacterial biofilms using fluorescent and chromogenic probes. J Indust Microbiol 16: 331–341.
[63]	Abedon ST (1992) Lysis of lysis inhibited bacteriophage T4-infected cells. J Bacteriol 174: 8073–8080.
[64]	Abedon ST (1989) Selection for bacteriophage latent period length by bacterial density: A theoretical examination. Microb Ecol 18: 79–88.
[65]	Wang IN, Dykhuizen DE, Slobodkin LB (1996) The evolution of phage lysis timing. Evol Ecol 10: 545–558.
[66]	Hadas H, Einav M, Fishov I, et al. (1997) Bacteriophage T4 development depends on the physiology of its host Escherichia coli. Microbiology 143: 179–185.
[67]	Abedon ST (2012) Bacterial "immunity" against bacteriophages. Bacteriophage 2: 50–54.
[68]	Koonin EV, Zhang F (2017) Coupling immunity and programmed cell suicide in prokaryotes: Life-or-death choices. BioEssays 39: 1–9.
[69]	Hoyland-Kroghsbo NM, Paczkowski J, Mukherjee S, et al. (2017) Quorum sensing controls the Pseudomonas aeruginosa CRISPR-Cas adaptive immune system. Proc Natl Acad Sci USA 114: 131–135.
[70]	Goldfarb T, Sberro H, Weinstock E, et al. (2015) BREX is a novel phage resistance system widespread in microbial genomes. EMBO J 34: 169–183.
[71]	Abedon ST (2015) Bacteriophage secondary infection. Virol Sin 30: 3–10.
[72]	McLean RJ, Corbin BD, Balzer GJ, et al. (2001) Phenotype characterization of genetically defined microorganisms and growth of bacteriophage in biofilms. Meth Enzymol 336: 163–174.
[73]	Azeredo J, Sutherland IW (2008) The use of phages for the removal of infectious biofilms. Curr Pharm Biotechnol 9: 261–266.
[74]	Sillankorva S, Azeredo J (2014) The use of bacteriophages and bacteriophage-derived enzymes for clinically relevant biofilm control, In: Borysowski, J., Miedzybrodzki, R., Górski, A. Editors, Phage Therapy: Current Research and Applications, Norfolk, UK: Caister Academic Press, 305–325.
[75]	Kutter E, Kellenberger E, Carlson K, et al. (1994) Effects of bacterial growth conditions and physiology on T4 infection, In: Karam, J.D., Kutter, E., Carlson, K., Guttman, B. Editors, The Molecular Biology of Bacteriophage T4, Washington, DC: ASM Press, 406–418.
[76]	Miller RV, Day M (2008) Contribution of lysogeny, pseudolysogeny, and starvation to phage ecology, In: Abedon, S.T. Editor, Bacteriophage Ecology, Cambridge, UK: Cambridge University Press, 114–143.
[77]	Pearl S, Gabay C, Kishony R, et al. (2008) Nongenetic individuality in the host-phage interaction. PLoS Biol 6: e120.
[78]	Abedon ST (2009) Disambiguating bacteriophage pseudolysogeny: an historical analysis of lysogeny, pseudolysogeny, and the phage carrier state, In: Adams, H.T. Editor, Contemporary Trends in Bacteriophage Research, Hauppauge, New York: Nova Science Publishers, 285–307.
[79]	Los M, Wegrzyn G (2012) Pseudolysogeny. Adv Virus Res 82: 339–349.
[80]	Golec P, Karczewska-Golec J, Los M, et al. (2014) Bacteriophage T4 can produce progeny virions in extremely slowly growing Escherichia coli host: comparison of a mathematical model with the experimental data. FEMS Microbiol Lett 351: 156–161.
[81]	Harper DR, Parracho HMR, Walker J, et al. (2014) Bacteriophages and biofilms. Antibiotics 3: 270–284.
[82]	Bryan D, el-Shibiny A, Hobbs Z, et al. (2016) Bacteriophage T4 infection of stationary phase E. coli: life after log from a phage perspective. Front Microbiol 7: 1391.
[83]	Yin J (1991) A quantifiable phenotype of viral propagation. Biochem Biophys Res Com 174: 1009–1014.
[84]	Filippini M, Buesing N, Bettarel Y, et al. (2006) Infection paradox: high abundance but low impact of freshwater benthic viruses. Appl Environ Microbiol 72: 4893–4898.
[85]	Wilkinson JF (1958) The extracellualr polysaccharides of bacteria. Bacteriol Rev 22: 46–73.
[86]	van Benthum WAJ, van Loosdrecht MCM, Tijhuis L, et al. (1995) Solids retention time in heterotrophic and nitrifying biofilms in a biofilm airlift suspension reactor. Water Sci Technol 32: 35–43.
[87]	Reichert P, Wanner O (1997) Movement of solids in biofilms-significance of liquid phase transport. Water Sci Technol 36: 321–328.
[88]	Davey ME, O'Toole GA (2000) Microbial biofilms: from ecology to molecular genetics. Microbiol Mol Biol Rev 64: 847–867.
[89]	Hanlon GW, Denyer SP, Olliff CJ, et al. (2001) Reduction in exopolysaccharide viscosity as an aid to bacteriophage penetration through Pseudomonas aeruginosa biofilms. Appl Environ Microbiol 67: 2746–2753.
[90]	Resch A, Fehrenbacher B, Eisele K, et al. (2005) Phage release from biofilm and planktonic Staphylococcus aureus cells. FEMS Microbiol Lett 252: 89–96.
[91]	Forde A, Fitzgerald GF (2003) Molecular organization of exopolysaccharide (EPS) encoding genes on the lactococcal bacteriophage adsorption blocking plasmid, pCI658. Plasmid 49: 130–142.
[92]	Flood JA, Ashbolt NJ (2000) Virus-sized particles can be entrapped and concentrated one hundred fold within wetland biofilms. Adv Environ Res 3: 403–411.
[93]	Storey MV, Ashbolt NJ (2001) Persistence of two model enteric viruses (B40-8 and MS-2 bacteriophages) in water distribution pipe biofilms. Water Sci Technol 43: 133–138.
[94]	Lacroix-Gueu P, Briandet R, Lévêque-Fort S, et al. (2005) In situ measurements of viral particles diffusion inside mucoid biofilms. C R Biol 328: 1065–1072.
[95]	Brüssow H (2013) Bacteriophage-host interaction: from splendid isolation into a messy reality. Curr Opin Microbiol 16: 500–506.
[96]	Fan X, Li W, Zheng F, et al. (2013) Bacteriophage inspired antibiotics discovery against infection involved biofilm. Crit Rev Eukaryot Gene Expr 23: 317–326.
[97]	Parasion S, Kwiatek M, Gryko R, et al. (2014) Bacteriophages as an alternative strategy for fighting biofilm development. Pol J Microbiol 63: 137–145.
[98]	Chan BK, Abedon ST (2015) Bacteriophages and their enzymes in biofilm control. Curr Pharm Des 21: 85–99.
[99]	Gutierrez D, Rodriguez-Rubio L, Martinez B, et al. (2016) Bacteriophages as weapons against bacterial biofilms in the food industry. Front Microbiol 7: 825.
[100]	Khalifa L, Shlezinger M, Beyth S, et al. (2016) Phage therapy against Enterococcus faecalis in dental root canals. J Oral Microbiol 8: 32157.
[101]	Motlagh AM, Bhattacharjee AS, Goel R (2016) Biofilm control with natural and genetically-modified phages. World J Microbiol Biotechnol 32: 67.
[102]	Abedon ST (2014) Phage therapy: eco-physiological pharmacology. Scientifica 2014: 581639.
[103]	Arber W, Linn S (1969) DNA modification and restriction. Annu Rev Biochem 38: 467–500.
[104]	Korona R, Levin BR (1993) Phage-mediated selection and the evolution and maintenance of restriction-modification. Evolution 47: 556–575.
[105]	Chao L, Levin BR, Stewart FM (1977) A complex community in a simple habitat: an experimental study with bacteria and phage. Ecology 58: 369–378.
[106]	Bohannan BJM, Travisano M, Lenski RE (1999) Epistatic interactions can lower the cost of resistance to multiple consumers. Evolution 53: 292–295.
[107]	Hill C (1993) Bacteriophage and bacteriophage resistance in lactic acid bacteria. FEMS Microbiol Rev 12: 87–108.
[108]	Nissen SB, Magidson T, Gross K, et al. (2016) Publication bias and the canonization of false facts. eLife 5: e21451.
[109]	Costerton JW, Cheng JJ, Geesey GG, et al. (1987) Bacterial biofilms in nature and disease. Ann Rev Microbiol 41: 435–464.
[110]	Oh YJ, Jo W, Yang Y, et al. (2007) Influence of culture conditions on Escherichia coli O157:H7 biofilm formation by atomic force microscopy. Ultramicroscopy 107: 869–874.
[111]	Cheng KJ, Costerton JW (1980) The formation of microcolonies by rumen bacteria. Can J Microbiol 26: 1104–1113.
[112]	Lacqua A, Wanner O, Colangelo T, et al. (2006) Emergence of biofilm-forming subpopulations upon exposure of Escherichia coli to environmental bacteriophages. Appl Environ Microbiol 72: 956–959.
[113]	Shen Y, Mitchell MS, Donovan DM, et al. (2012) Phage-based enzybiotics, In: Hyman, P., Abedon, S.T. Editors, Bacteriophages in Health and Disease, Wallingford, UK: CABI Press, 217–239.
[114]	Yan J, Mao J, Xie J (2014) Bacteriophage polysaccharide depolymerases and biomedical applications. BioDrugs 28: 265–274.
[115]	Gutiérrez D, Briers Y, Rodríguez-Rubio L, et al. (2015) Role of the pre-neck appendage protein (Dpo7) from phage vB_SepiS-phiIPLA7 as an anti-biofilm agent in staphylococcal species. Front Microbiol 6: 1315.
[116]	Pires DP, Oliveira H, Melo LD, et al. (2016) Bacteriophage-encoded depolymerases: their diversity and biotechnological applications. Appl Microbiol Biotechnol 100: 2141–2151.
[117]	Westra ER, van HS, Oyesiku-Blakemore S, et al. (2015) Parasite exposure drives selective evolution of constitutive versus inducible defense. Curr Biol 25: 1043–1049.
[118]	Berngruber TW, Lion S, Gandon S (2013) Evolution of suicide as a defence strategy against pathogens in a spatially structured environment. Ecol Lett 16: 446–453.
[119]	Refardt D, Kummerli R (2013) Defying bacteriophages: contrasting altruistic with individual-based resistance mechanisms in Escherichia coli. Commun Integr Biol 6: e25159.
[120]	Heilmann S, Sneppen K, Krishna S (2012) Coexistence of phage and bacteria on the boundary of self-organized refuges. Proc Natl Acad Sci USA 109: 12828–12833.
[121]	Abedon ST, Kuhl SJ, Blasdel BG, et al. (2011) Phage treatment of human infections. Bacteriophage 1: 66–85.
[122]	Borysowski J, Miedzybrodzki R, Górski A (2014) Phage Therapy: Current Research and Applications, Norfolk, UK: Caister Academic Press.
[123]	Scali C, Kunimoto B (2013) An update on chronic wounds and the role of biofilms. J Cutan Med Surg 17: 371–376.
[124]	Cooper RA, Bjarnsholt T, Alhede M (2014) Biofilms in wounds: a review of present knowledge. J Wound Care 23: 570–580.
[125]	Macia MD, Rojo-Molinero E, Oliver A (2014) Antimicrobial susceptibility testing in biofilm-growing bacteria. Clin Microbiol Infect 20: 981–990.
[126]	Abedon ST (2015) Phage therapy of pulmonary infections. Bacteriophage 5: e1020260.
[127]	Fish R, Kutter E, Wheat G, et al. (2016) Bacteriophage treatment of intransigent diabetic toe ulcers: a case series. J Wound Care 25: S27–S33.
[128]	Abedon ST (2017) Bacteriophage clinical use as antibactertial "drugs": utility precident. Microbiol Spectr.
[129]	Stewart PS, Franklin MJ (2008) Physiological heterogeneity in biofilms. Nat Rev Microbiol 6: 199–210.
[130]	Davis KM, Mohammadi S, Isberg RR (2015) Community behavior and spatial regulation within a bacterial microcolony in deep tissue sites serves to protect against host attack. Cell Host Microbe 17: 21–31.
[131]	Harmsen M, Yang L, Pamp SJ, et al. (2010) An update on Pseudomonas aeruginosa biofilm formation, tolerance, and dispersal. FEMS Immunol Med Microbiol 59: 253–268.
[132]	Purevdorj-Gage B, Costerton WJ, Stoodley P (2005) Phenotypic differentiation and seeding dispersal in non-mucoid and mucoid Pseudomonas aeruginosa biofilms. Microbiology 151: 1569–1576.
[133]	Hamilton WA (1987) Biofilms: microbial interactions and metabolic activities, In: Fletcher, M., Gray, T.R.G., Jones, J.G. Editors, Ecology of Microbial Communities, Cambridge: Cambridge University Press, 361–385.
[134]	Abedon ST, Herschler TD, Stopar D (2001) Bacteriophage latent-period evolution as a response to resource availability. Appl Environ Microbiol 67: 4233–4241.
[135]	Levin BR, Bull JJ (2004) Population and evolutionary dynamics of phage therapy. Nat Rev Microbiol 2: 166–173.
[136]	Gill JJ (2008) Modeling of bacteriophage therapy, In: Abedon, S.T. Editor, Bacteriophage Ecology, Cambridge, UK: Cambridge University Press, 439–464.
[137]	Stent GS (1963) Molecular Biology of Bacterial Viruses, San Francisco, CA: WH Freeman and Co.
[138]	Gallet R, Shao Y, Wang IN (2009) High adsorption rate is detrimental to bacteriophage fitness in a biofilm-like environment. BMC Evol Biol 9: 241.
[139]	Yin J, McCaskill JS (1992) Replication of viruses in a growing plaque: a reaction-diffusion model. Biophys J 61: 1540–1549.
[140]	Abedon ST, Culler RR (2007) Bacteriophage evolution given spatial constraint. J Theor Biol 248: 111–119.
[141]	Hewson I, Fuhrman JA (2003) Viriobenthos production and virioplankton sorptive scavenging. Microb Ecol 46: 337–347.
[142]	Hoyland-Kroghsbo NM, Maerkedahl RB, Svenningsen SL (2013) A quorum-sensing-induced bacteriophage defense mechanism. MBio 4: e00362.
[143]	Boots M, Mealor M (2007) Local interactions select for lower pathogen infectivity. Science 315: 1284–1286.
[144]	Abedon ST (2016) Commentary: phage therapy of staphylococcal chronic osteomyelitis in experimental animal model. Front Microbiol 7: 1251.
[145]	Kutter E, De Vos D, Gvasalia G, et al. (2010) Phage therapy in clinical practice: treatment of human infections. Curr Pharm Biotechnol 11: 69–86.
[146]	Hyman P, Abedon ST (2009) Practical methods for determining phage growth parameters. Meth Mol Biol 501: 175–202.
[147]	Mirzaei MK, Nilsson AS (2015) Isolation of phages for phage therapy: a comparison of spot tests and efficiency of plating analyses for determination of host range and efficacy. PLoS One 10: e0118557.
[148]	Abedon ST (2014) Bacteriophages as drugs: the pharmacology of phage therapy, In: Borysowski, J., Miedzybrodzki, R., Górski, A. Editors, Phage Therapy: Current Research and Applications, Norfolk, UK: Caister Academic Press, 69–100.

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