Peculiarities of Staphylococcus aureus phages and their possible application in phage therapy

  • Aa Haeruman Azam
  • Yasunori TanjiEmail author


Bacteriophage has become an attractive alternative for the treatment of antibiotic-resistant Staphylococcus aureus. For the success of phage therapy, phage host range is an important criterion when considering a candidate phage. Most reviews of S. aureus (SA) phages have focused on their impact on host evolution, especially their contribution to the spread of virulence genes and pathogenesis factors. The potential therapeutic use of SA phages, especially detailed characterizations of host recognition mechanisms, has not been extensively reviewed so far. In this report, we provide updates on the study of SA phages, focusing on host recognition mechanisms with the recent discovery of phage receptor-binding proteins (RBPs) and the possible applications of SA phages in phage therapy.


Staphylococcal phage Phage therapy Host recognition mechanism Receptor-binding protein 



The first author would like to thank the Ministry of Education, Culture, Sports, Science and Technology of Japan for providing a scholarship during his doctoral study.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Ethical approval

This article does not contain any studies with human participants or animal performed by any of the authors.


  1. Abedon ST, Kuhl SJ, Blasdel BG, Kutter EM (2011) Phage treatment of human infections. Bacteriophage 1:66–85. CrossRefGoogle Scholar
  2. Ajuebor J, Buttimer C, Arroyo-Moreno S, Chanishvili N, Gabriel E, O’Mahony J, McAuliffe O, Neve H, Franz C, Coffey A (2018) Comparison of Staphylococcus phage K with close phage relatives commonly employed in phage therapeutics. Antibiotics 7:37. CrossRefGoogle Scholar
  3. Alves DR, Gaudion A, Bean JE, Perez Esteban P, Arnot TC, Harper DR, Kot W, Hansen LH, Enright MC, Jenkins ATA (2014) Combined use of bacteriophage K and a novel bacteriophage to reduce Staphylococcus aureus biofilm formation. Appl Environ Microbiol 80:6694–6703. CrossRefGoogle Scholar
  4. Azam AH (2019) Analysis of phage resistance mechanism of Staphylococcus aureus SA003 which causes bovine mastitis against phages ɸSA012 and ɸSA039. Dissertation, Tokyo Institute of TechnologyGoogle Scholar
  5. Azam AH, Tanji Y (2019) Bacteriophage-host arm race: an update on the mechanism of phage resistance in bacteria and revenge of the phage with the perspective for phage therapy. Appl Microbiol Biotechnol 103(5):2121–2131.
  6. Azam AH, Hoshiga F, Takeuchi I, Miyanaga K, Tanji Y (2018) Analysis of phage resistance in Staphylococcus aureus SA003 reveals different binding mechanisms for the closely related Twort-like phages ɸSA012 and ɸSA039. Appl Microbiol Biotechnol 102(20):8963–8977CrossRefGoogle Scholar
  7. Brown S, Xia G, Luhachack LG, Campbell J, Meredith TC, Chen C, Winstel V, Gekeler C, Irazoqui JE, Peschel A, Walker S (2012) Methicillin resistance in Staphylococcus aureus requires glycosylated wall teichoic acids. Proc Natl Acad Sci 109:18909–18914. CrossRefGoogle Scholar
  8. Brown S, Santa Maria JP, Walker S (2013) Wall teichoic acids of Gram-positive bacteria. Annu Rev Microbiol 67:313–336. CrossRefGoogle Scholar
  9. Brussow H, Canchaya C, Hardt W-D (2004) Phages and the evolution of bacterial pathogens: from genomic rearrangements to lysogenic conversion. Microbiol Mol Biol Rev 68:560–602. CrossRefGoogle Scholar
  10. Capparelli R, Parlato M, Borriello G, Salvatore P, Iannelli D (2007) Experimental phage therapy against Staphylococcus aureus in mice. Antimicrob Agents Chemother 51:2765–2773. CrossRefGoogle Scholar
  11. Chan BK, Abedon ST, Loc-Carrillo C (2013) Phage cocktails and the future of phage therapy. Future Microbiol 8:769–783CrossRefGoogle Scholar
  12. Cui Z, Song Z, Wang Y, Zeng L, Shen W, Wang Z, Li Q, He P, Qin J, Guo X (2012) Complete genome sequence of wide-host-range Staphylococcus aureus phage JD007. J Virol 86:13880–13881. CrossRefGoogle Scholar
  13. Cui Z, Guo X, Dong K, Zhang Y, Li Q, Zhu Y, Zeng L, Tang R, Li L (2017) Safety assessment of Staphylococcus phages of the family Myoviridae based on complete genome sequences. Sci Rep 7:41259. CrossRefGoogle Scholar
  14. Deghorain M, Van Melderen L (2012) The staphylococci phages family: an overview. Viruses 4:3316–3335CrossRefGoogle Scholar
  15. Dunne M, Hupfeld M, Klumpp J, Loessner MJ (2018) Molecular basis of bacterial host interactions by Gram-positive targeting bacteriophages. Viruses 10:8CrossRefGoogle Scholar
  16. Dvořáčková M, Růžička F, Benešík M, Pantůček R, Dvořáková-Heroldová M (2018) Antimicrobial effect of commercial phage preparation Stafal® on biofilm and planktonic forms of methicillin-resistant Staphylococcus aureus. Folia Microbiol 64:121–126. Google Scholar
  17. El Haddad L, Ben AN, Plante PL, Dumaresq J, Katsarava R, Labrie S, Corbeil J, St-Gelais D, Moineau S (2014) Improving the safety of Staphylococcus aureus polyvalent phages by their production on a Staphylococcus xylosus strain. PLoS One 9:7. Google Scholar
  18. Enault F, Briet A, Bouteille L, Roux S, Sullivan MB, Petit MA (2017) Phages rarely encode antibiotic resistance genes: a cautionary tale for virome analyses. ISME J 11:237–247. CrossRefGoogle Scholar
  19. Endl J, Seidl HP, Fiedler F, Schleifer KH (1983) Chemical composition and structure of cell wall teichoic acids of staphylococci. Arch Microbiol 135:215–223. CrossRefGoogle Scholar
  20. Enright MC, Robinson DA, Randle G, Feil EJ, Grundmann H, Spratt BG, Walsh CT (2002) The evolutionary history of methicillin-resistant Staphylococcus aureus (MRSA). Proc Natl Acad Sci 99:7687–7692CrossRefGoogle Scholar
  21. Feil EJ, Cooper JE, Grundmann H, Robinson DA, Enright MC, Berendt T, Peacock SJ, Smith JM, Murphy M, Spratt BG, Moore CE, Day NPJ (2003) How clonal is Staphylococcus aureus? J Bacteriol 185:3307–3316. CrossRefGoogle Scholar
  22. Fischetti VA (2010) Bacteriophage endolysins: a novel anti-infective to control Gram-positive pathogens. Int J Med Microbiol 300:357–362CrossRefGoogle Scholar
  23. Fish R, Kutter E, Wheat G, Blasdel B, Kutateladze M, Kuhl S (2016) Bacteriophage treatment of intransigent diabetic toe ulcers: a case series. J Wound Care 25:S27–S33. CrossRefGoogle Scholar
  24. Fujiki J, Nakamura T, Furusawa T, Ohno H, Takahashi H, Kitana J, Usui M, Higuchi H, Tanji Y, Tamura Y, Iwano H (2018) Characterization of the lytic capability of a lysk-like endolysin, lys-phiSA012, derived from a polyvalent Staphylococcus aureus bacteriophage. Pharmaceuticals 11(1).
  25. García P, Martínez B, Obeso JM, Lavigne R, Lurz R, Rodríguez A (2009) Functional genomic analysis of two Staphylococcus aureus phages isolated from the dairy environment. Appl Environ Microbiol 75:7663–7673. CrossRefGoogle Scholar
  26. Gerlach D, Guo Y, De Castro C, Kim S-H, Schlatterer K, Xu F-F, Pereira C, Seeberger PH, Ali S, Codée J, Sirisarn W, Schulte B, Wolz C, Larsen J, Molinaro A, Lee BL, Xia G, Stehle T, Peschel A (2018) Methicillin-resistant Staphylococcus aureus alters cell wall glycosylation to evade immunity. Nature 563:705–709. CrossRefGoogle Scholar
  27. Hsieh SE, Lo HH, Chen ST, Lee MC, Tseng YH (2011) Wide host range and strong lytic activity of Staphylococcus aureus lytic phage Stau2. Appl Environ Microbiol 77:756–761. CrossRefGoogle Scholar
  28. Iwano H, Inoue Y, Takasago T, Kobayashi H, Furusawa T, Taniguchi K, Fujiki J, Yokota H, Usui M, Tanji Y, Hagiwara K, Higuchi H, Tamura Y (2018) Bacteriophage ΦSA012 has a broad host range against Staphylococcus aureus and effective lytic capacity in a mouse mastitis model. Biology 7:8. CrossRefGoogle Scholar
  29. Jikia D, Chkhaidze N, Imedashvili E, Mgaloblishvili I, Tsitlanadze G, Katsarava R, Morris JG, Sulakvelidze A (2005) The use of a novel biodegradable preparation capable of the sustained release of bacteriophages and ciprofloxacin, in the complex treatment of multidrug-resistant Staphylococcus aureus-infected local radiation injuries caused by exposure to Sr90. Clin Exp Dermatol 30:23–26. CrossRefGoogle Scholar
  30. Kaneko J, Narita-Yamada S, Wakabayashi Y, Kamio Y (2009) Identification of ORF636 in phage φSLT carrying Panton-Valentine leukocidin genes, acting as an adhesion protein for a poly(glycerophosphate) chain of lipoteichoic acid on the cell surface of Staphylococcus aureus. J Bacteriol 191:4674–4680. CrossRefGoogle Scholar
  31. Khairullin IN, Pozdeev OK, Shaimordanov R (2002) Efficiency of using specific bacteriophages in the treatment and prophylaxis of surgical postoperative infections. Kazan Med J 83:258–261 [Article in Russian]Google Scholar
  32. Kloos WE, Bannerman TL (1994) Update on clinical significance of coagulase-negative staphylococci. Clin Microbiol Rev 7:117–140CrossRefGoogle Scholar
  33. Kumaran D, Taha M, Yi QL, Ramirez-Arcos S, Diallo JS, Carli A, Abdelbary H (2018) Does treatment order matter? Investigating the ability of bacteriophage to augment antibiotic activity against Staphylococcus aureus biofilms. Front Microbiol 9:127. CrossRefGoogle Scholar
  34. Kvachadze L, Balarjishvili N, Meskhi T, Tevdoradze E, Skhirtladze N, Pataridze T, Adamia R, Topuria T, Kutter E, Rohde C, Kutateladze M (2011) Evaluation of lytic activity of staphylococcal bacteriophage Sb-1 against freshly isolated clinical pathogens. Microb Biotechnol 4:643–650. CrossRefGoogle Scholar
  35. Kwan T, Liu J, DuBow M, Gros P, Pelletier J (2005) The complete genomes and proteomes of 27 Staphylococcus aureus bacteriophages. Proc Natl Acad Sci 102:5174–5179. CrossRefGoogle Scholar
  36. Leskinen K, Tuomala H, Wicklund A, Horsma-Heikkinen J, Kuusela P, Skurnik M, Kiljunen S (2017) Characterization of vB_SauM-fRuSau02, a Twort-like bacteriophage isolated from a therapeutic phage cocktail. Viruses 9:258. CrossRefGoogle Scholar
  37. Li X, Gerlach D, Du X, Larsen J, Stegger M, Kuhner P, Peschel A, Xia G, Winstel V (2015) An accessory wall teichoic acid glycosyltransferase protects Staphylococcus aureus from the lytic activity of Podoviridae. Sci Rep 5:17219. CrossRefGoogle Scholar
  38. Li X, Koç C, Kühner P, Stierhof Y-D, Krismer B, Enright MC, Penadés JR, Wolz C, Stehle T, Cambillau C, Peschel A, Xia G (2016) An essential role for the baseplate protein Gp45 in phage adsorption to Staphylococcus aureus. Nat Publ Gr 6:26455. Google Scholar
  39. Lindsay JA (2010) Genomic variation and evolution of Staphylococcus aureus. Int J Med Microbiol 300:98–103CrossRefGoogle Scholar
  40. Liu J, Dehbi M, Moeck G, Arhin F, Bauda P, Bergeron D, Callejo M, Ferretti V, Ha N, Kwan T, McCarty J, Srikumar R, William D, Wu JJ, Gros P, Pelletier J, Dubow M (2004) Antimicrobial drug discovery through bacteriophage genomics. Nat Biotechnol 22:185–191CrossRefGoogle Scholar
  41. Lobocka M, Hejnowicz MS, Dabrowski K, Gozdek A, Kosakowski J, Witkowska M, Ulatowska MI, Weber-Dabrowska B, Kwiatek M, Parasion S, Gawor J, Kosowska H, Glowacka A (2012) Genomics of staphylococcal Twort-like phages potential therapeutics of the post-antibiotic era. Adv Virus Res 83:143–216. CrossRefGoogle Scholar
  42. Maciejewska B, Olszak T, Drulis-Kawa Z (2018) Applications of bacteriophages versus phage enzymes to combat and cure bacterial infections: an ambitious and also a realistic application? Appl Microbiol Biotechnol 102:2563–2581CrossRefGoogle Scholar
  43. Martínez-Rubio R, Quiles-Puchalt N, Martí M, Humphrey S, Ram G, Smyth D, Chen J, Novick RP, Penadés JR (2017) Phage-inducible islands in the Gram-positive cocci. ISME J 11:1029–1042. CrossRefGoogle Scholar
  44. Matsuzaki S, Yasuda M, Nishikawa H, Kuroda M, Ujihara T, Shuin T, Shen Y, Jin Z, Fujimoto S, Nasimuzzaman MD, Wakiguchi H, Sugihara S, Sugiura T, Koda S, Muraoka A, Imai S (2003) Experimental protection of mice against lethal Staphylococcus aureus infection by novel bacteriophage φMR11. J Infect Dis 187:613–624. CrossRefGoogle Scholar
  45. McCallin S, Sarker SA, Sultana S, Oechslin F, Brüssow H (2018) Metagenome analysis of Russian and Georgian Pyophage cocktails and a placebo-controlled safety trial of single phage versus phage cocktail in healthy Staphylococcus aureus carriers. Environ Microbiol 20:3278–3293. CrossRefGoogle Scholar
  46. McCarthy AJ, Witney AA, Lindsay JA (2012) Staphylococcus aureus temperate bacteriophage: carriage and horizontal gene transfer is lineage associated. Front Cell Infect Microbiol 2:6. CrossRefGoogle Scholar
  47. Melo LDR, Brandão A, Akturk E, Santos SB, Azeredo J (2018) Characterization of a new Staphylococcus aureus Kayvirus harboring a lysin active against biofilms. Viruses 10:182. CrossRefGoogle Scholar
  48. Meredith TC, Swoboda JG, Walker S (2008) Late-stage polyribitol phosphate wall teichoic acid biosynthesis in Staphylococcus aureus. J Bacteriol 190:3046–3056. CrossRefGoogle Scholar
  49. Moodley A, Kot W, Nälgård S, Jakociune D, Neve H, Hansen LH, Guardabassi L, Vogensen FK (2018) Isolation and characterization of bacteriophages active against methicillin-resistant Staphylococcus pseudintermedius. Res Vet Sci 122:81–85. CrossRefGoogle Scholar
  50. Morozova VV, Vlassov VV, Tikunova NV (2018) Applications of bacteriophages in the treatment of localized infections in humans. Front Microbiol 9:1696CrossRefGoogle Scholar
  51. Nobrega FL, Vlot M, de Jonge PA, Dreesens LL, Beaumont HJE, Lavigne R, Dutilh BE, Brouns SJJ (2018) Targeting mechanisms of tailed bacteriophages. Nat Rev Microbiol 16:760–773. CrossRefGoogle Scholar
  52. O’Flaherty S, Coffey A, Edwards R, Meaney W, Fitzgerald GF, Ross RP (2004) Genome of staphylococcal phage K: a new lineage of Myoviridae infecting Gram-positive bacteria with a low G+C content. J Bacteriol 186:2862–2871. CrossRefGoogle Scholar
  53. O’Flaherty S, Ross RP, Coffey A (2009) Bacteriophage and their lysins for elimination of infectious bacteria: review article. FEMS Microbiol Rev 33:801–819CrossRefGoogle Scholar
  54. Pantůček R, Doškař J, Růžičková V, Kašpárek P, Oráčová E, Kvardová V, Rosypal S (2004) Identification of bacteriophage types and their carriage in Staphylococcus aureus. Arch Virol 149:1689–1703. CrossRefGoogle Scholar
  55. Pincus NB, Reckhow JD, Saleem D, Jammeh ML, Datta SK, Myles IA (2015) Strain specific phage treatment for Staphylococcus aureus infection is influenced by host immunity and site of infection. PLoS One 10:1371. CrossRefGoogle Scholar
  56. Pollackt JH, Neuhaus FC (1994) Changes in wall teichoic acid during the rod-sphere transition of Bacillus subtilis 168. J Bacteriol 176:7252–7259. CrossRefGoogle Scholar
  57. Pompilio A, De Nicola S, Crocetta V, Guarnieri S, Savini V, Carretto E, Di Bonaventura G (2015) New insights in Staphylococcus pseudintermedius pathogenicity: antibiotic-resistant biofilm formation by a human wound-associated strain. BMC Microbiol 15:109. CrossRefGoogle Scholar
  58. Rashel M, Uchiyama J, Ujihara T, Uehara Y, Kuramoto S, Sugihara S, Yagyu K, Muraoka A, Sugai M, Hiramatsu K, Honke K, Matsuzaki S (2007) Efficient elimination of multidrug-resistant Staphylococcus aureus by cloned Lysin derived from bacteriophage φMR11. J Infect Dis 196:1237–1247. CrossRefGoogle Scholar
  59. Rippon JE (1956) The classification of bacteriophages lysing staphylococci. J Hyg 54:213–226. CrossRefGoogle Scholar
  60. Sakoulas G, Eliopoulos GM, Fowler VG, Moellering RC, Novick RP, Lucindo N, Yeaman MR, Bayer AS (2005) Reduced susceptibility of Staphylococcus aureus to vancomycin and platelet microbicidal protein correlates with defective autolysis and loss of accessory gene regulator (agr) function. Antimicrob Agents Chemother 49:2687–2692. CrossRefGoogle Scholar
  61. Schmelcher M, Loessner MJ (2014) Application of bacteriophages for detection of foodborne pathogens. Bacteriophage 4:28137CrossRefGoogle Scholar
  62. Shaw DR, Chatterjee AN (1971) O-Acetyl groups as a component of the bacteriophage receptor on Staphylococcus aureus cell walls. J Bacteriol 108:584–585Google Scholar
  63. Sunagar R, Patil SA, Chandrakanth RK (2010) Bacteriophage therapy for Staphylococcus aureus bacteremia in streptozotocin-induced diabetic mice. Res Microbiol 161:854–860. CrossRefGoogle Scholar
  64. Synnott AJ, Kuang Y, Kurimoto M, Yamamichi K, Iwano H, Tanji Y (2009) Isolation from sewage influent and characterization of novel Staphylococcus aureus bacteriophages with wide host ranges and potent lytic capabilities. Appl Environ Microbiol 75:4483–4490. CrossRefGoogle Scholar
  65. Takemura-Uchiyama I, Uchiyama J, ichiro KS, Inoue T, Ujihara T, Ohara N, Daibata M, Matsuzaki S (2013) Evaluating efficacy of bacteriophage therapy against Staphylococcus aureus infections using a silkworm larval infection model. FEMS Microbiol Lett 347:52–60CrossRefGoogle Scholar
  66. Takemura-Uchiyama I, Uchiyama J, Osanai M, Morimoto N, Asagiri T, Ujihara T, Daibata M, Sugiura T, Matsuzaki S (2014) Experimental phage therapy against lethal lung-derived septicemia caused by Staphylococcus aureus in mice. Microbes Infect 16:512–517. CrossRefGoogle Scholar
  67. Takeuchi I, Osada K, Azam AH, Asakawa H, Miyanaga K, Tanji Y (2016) The presence of two receptor-binding proteins contributes to the wide host range of staphylococcal Twort-like phages. Appl Environ Microbiol 82:5763–5774. CrossRefGoogle Scholar
  68. Tanji Y, Shimada T, Yoichi M, Miyanaga K, Hori K, Unno H (2004) Toward rational control of Escherichia coli O157:H7 by a phage cocktail. Appl Microbiol Biotechnol 64:270–274. CrossRefGoogle Scholar
  69. Tanji Y, Shimada T, Fukudomi H, Miyanaga K, Nakai Y, Unno H (2005) Therapeutic use of phage cocktail for controlling Escherichia coli O157:H7 in gastrointestinal tract of mice. J Biosci Bioeng 100:280–287. CrossRefGoogle Scholar
  70. Tong SYC, Davis JS, Eichenberger E, Holland TL, Fowler VG (2015) Staphylococcus aureus infections: epidemiology, pathophysiology, clinical manifestations, and management. Clin Microbiol Rev 28:603–661. CrossRefGoogle Scholar
  71. Uchiyama J, Takemura-UchiyAma I, Kato SI, Sato M, Ujihara T, Matsui H, Hanaki H, Daibata M, Matsuzaki S (2014) In silico analysis of AHJD-like viruses, Staphylococcus aureus phages S24-1 and S13’, and study of phage S24-1 adsorption. MicrobiologyOpen 3:257–270. CrossRefGoogle Scholar
  72. Uchiyama J, Taniguchi M, Kurokawa K, Takemura-Uchiyama I, Ujihara T, Shimakura H, Sakaguchi Y, Murakami H, Sakaguchi M, Matsuzaki S (2017) Adsorption of Staphylococcus viruses S13′ and S24-1 on Staphylococcus aureus strains with different glycosidic linkage patterns of wall teichoic acids. J Gen Virol 98:2171–2180. CrossRefGoogle Scholar
  73. Utter B, Deutsch DR, Schuch R, Winer BY, Verratti K, Bishop-Lilly K, Sozhamannan S, Fischetti VA (2014) Beyond the chromosome: the prevalence of unique extra-chromosomal bacteriophages with integrated virulence genes in pathogenic Staphylococcus aureus. PLoS One 9:6. CrossRefGoogle Scholar
  74. Vandersteegen K, Mattheus W, Ceyssens P-J, Bilocq F, De Vos D, Pirnay J-P, Noben J-P, Merabishvili M, Lipinska U, Hermans K, Lavigne R (2011) Microbiological and molecular assessment of bacteriophage ISP for the control of Staphylococcus aureus. PLoS One 6:24418. CrossRefGoogle Scholar
  75. Winstel V, Liang C, Sanchez-Carballo P, Steglich M, Munar M, Broker BM, Penadés JR, Nübel U, Holst O, Dandekar T, Peschel A, Xia G (2013) Wall teichoic acid structure governs horizontal gene transfer between major bacterial pathogens. Nat Commun 4:2345. CrossRefGoogle Scholar
  76. Winstel V, Sanchez-Carballo P, Holst O, Xia G, Peschel A (2014) Biosynthesis of the unique wall teichoic acid of Staphylococcus aureus lineage ST395. MBio 5:2. CrossRefGoogle Scholar
  77. Xia G, Wolz C (2014) Phages of Staphylococcus aureus and their impact on host evolution. Infect Genet Evol 21:593–601. CrossRefGoogle Scholar
  78. Xia G, Maier L, Sanchez-Carballo P, Li M, Otto M, Holst O, Peschel A (2010) Glycosylation of wall teichoic acid in Staphylococcus aureus by TarM. J Biol Chem 285:13405–13415. CrossRefGoogle Scholar
  79. Xia G, Corrigan RM, Winstel V, Goerke C, Gründling A, Peschel A (2011) Wall teichoic acid-dependent adsorption of staphylococcal siphovirus and myovirus. J Bacteriol 193:4006–4009. CrossRefGoogle Scholar

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© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.School of Life Science and TechnologyTokyo Institute of TechnologyYokohamaJapan

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