Are phage lytic proteins the secret weapon to kill staphylococcus aureus?

mBio

Volumn 9, Issue 1, 2018, Pages

  Gutiérrez, Diana ^a   Fernández, Lucía ^a   Rodríguez, Ana ^a   García, Pilar ^a  

^a DEPARTMENT OF MICROBIOLOGY AND BIOCHEMISTRY OF DAIRY PRODUCTS   (Spain)

Author keywords

Bacteriophage; Bacteriophage therapy; Endolysin; Staphylococcus aureus

Indexed keywords

ANTIINFECTIVE AGENT; CHIMERIC PROTEIN; DAPTOMYCIN; ENDOLYSIN; LYSOSTAPHIN; MINOCYCLINE; PHAGE LYTIC PROTEIN; PHYTOHEMAGGLUTININ; PROTEIN CF301; PROTEIN P128; PROTEIN SAL200; UNCLASSIFIED DRUG; VIRION ASSOCIATED PEPTIDOGLYCAN HYDROLASE; N ACETYLMURAMOYLALANINE AMIDASE; PROTEINASE; VIRAL PROTEIN;

ANTIBIOFILM ACTIVITY; ANTIBIOTIC RESISTANCE; BACTEREMIA; BACTERIAL CLEARANCE; BACTERIAL STRAIN; BACTERICIDAL ACTIVITY; BACTERIOPHAGE; CARBOXY TERMINAL SEQUENCE; CELLULAR IMMUNITY; COMBINATION CHEMOTHERAPY; DISEASE MODEL; DOWN REGULATION; DRUG ACTIVITY; DRUG CYTOTOXICITY; DRUG EFFECT; DRUG EFFICACY; DRUG FORMULATION; DRUG MANUFACTURE; DRUG MECHANISM; DRUG SAFETY; DRUG TOLERABILITY; DRUG USE; ENZYME ACTIVE SITE; ENZYME ACTIVITY; FOOD SAFETY; GOVERNMENT REGULATION; HUMAN; METHICILLIN RESISTANT STAPHYLOCOCCUS AUREUS; METHICILLIN RESISTANT STAPHYLOCOCCUS AUREUS INFECTION; MORTALITY RATE; MTT ASSAY; NONHUMAN; PRIORITY JOURNAL; PROTEIN MODIFICATION; PROTEIN STRUCTURE; SHORT SURVEY; STRUCTURE ACTIVITY RELATION; STRUCTURE ANALYSIS; CLINICAL TRIAL (TOPIC); DRUG APPROVAL; ENZYMOLOGY; PRECLINICAL STUDY; STAPHYLOCOCCUS INFECTION; STAPHYLOCOCCUS PHAGE;

CLINICAL TRIALS AS TOPIC; DRUG APPROVAL; DRUG EVALUATION, PRECLINICAL; ENDOPEPTIDASES; HUMANS; N-ACETYLMURAMOYL-L-ALANINE AMIDASE; STAPHYLOCOCCAL INFECTIONS; STAPHYLOCOCCUS PHAGES; VIRAL PROTEINS;

EID: 85043511801     PISSN: 21612129     EISSN: 21507511     Source Type: Journal    
DOI: 10.1128/mBio.01923-17     Document Type: Short Survey

References (91)

1. WHO. 2014. Antimicrobial resistance, global report on surveillance 2014. WHO, Geneva, Switzerland.
2. Le Loir Y, Baron F, Gautier M. 2003. Staphylococcus aureus and food poisoning. Genet Mol Res 2:63–76.
3. EFSA, ECDC. 2016. The European Union summary report on trends and sources of zoonoses, zoonotic agents and food-borne outbreaks in 2014. EFSA J 13:4329.
4. Normanno G, Dambrosio A, Lorusso V, Samoilis G, Di Taranto P, Parisi A. 2015. Methicillin-resistant Staphylococcus aureus (MRSA) in slaughtered pigs and abattoir workers in Italy. Food Microbiol 51:51–56. https://doi.org/10.1016/j.fm.2015.04.007.
5. Aminov R. 2017. History of antimicrobial drug discovery: major classes and health impact. Biochem Pharmacol 133:4–19. https://doi.org/10.1016/j.bcp.2016.10.001.
6. WHO. 2012. The evolving threat of antimicrobial resistance: options for action. World Health Organization, Geneva, Switzerland.
7. Maron DF, Smith TJ, Nachman KE. 2013. Restrictions on antimicrobial use in food animal production: an international regulatory and economic survey. Global Health 9:48. https://doi.org/10.1186/1744-8603-9-48.
8. Catalão MJ, Gil F, Moniz-Pereira J, são-José C, Pimentel M. 2013. Diversity in bacterial lysis systems: bacteriophages show the way. FEMS Microbiol Rev 37:554–571. https://doi.org/10.1111/1574-6976.12006.
9. Sulakvelidze A, Morris JG, Jr. 2001. Bacteriophages as therapeutic agents. Ann Med 33:507–509. https://doi.org/10.3109/07853890108995959.
10. Fischetti VA. 2008. Bacteriophage lysins as effective antibacterials. Curr Opin Microbiol 11:393– 400. https://doi.org/10.1016/j.mib.2008.09.012.
11. Rodríguez-Rubio L, Martínez B, Donovan DM, Rodríguez A, García P. 2013. Bacteriophage virion-associated peptidoglycan hydrolases: potential new enzybiotics. Crit Rev Microbiol 39:427– 434. https://doi.org/10.3109/1040841X.2012.723675.
12. Clark JR, March JB. 2004. Bacterial viruses as human vaccines? Expert Rev Vaccines 3:463– 476. https://doi.org/10.1586/14760584.3.4.463.
13. Oliveira H, Melo LD, Santos SB, Nóbrega FL, Ferreira EC, Cerca N, Azeredo J, Kluskens LD. 2013. Molecular aspects and comparative genomics of bacteriophage endolysins. J Virol 87:4558–4570. https://doi.org/10.1128/JVI.03277-12.
14. Vollmer W, Joris B, Charlier P, Foster S. 2008. Bacterial peptidoglycan (murein) hydrolases. FEMS Microbiol Rev 32:259–286. https://doi.org/10.1111/j.1574-6976.2007.00099.x.
15. Becker SC, Foster-Frey J, Stodola AJ, Anacker D, Donovan DM. 2009. Differentially conserved staphylococcal SH3b_5 cell wall binding domains confer increased staphylolytic and streptolytic activity to a streptococcal prophage endolysin domain. Gene 443:32– 41. https://doi.org/10.1016/j.gene.2009.04.023.
16. Gründling A, Schneewind O. 2006. Cross-linked peptidoglycan mediates lysostaphin binding to the cell wall envelope of Staphylococcus aureus. J Bacteriol 188:2463–2472. https://doi.org/10.1128/JB.188.7.2463-2472.2006.
17. Daniel A, Euler C, Collin M, Chahales P, Gorelick KJ, Fischetti VA. 2010. Synergism between a novel chimeric lysin and oxacillin protects against infection by methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 54:1603–1612. https://doi.org/10.1128/AAC.01625-09.
18. Chang Y, Ryu S. 2017. Characterization of a novel cell wall binding domain-containing Staphylococcus aureus endolysin LysSA97. Appl Microbiol Biotechnol 101:147–158. https://doi.org/10.1007/s00253-016 -7747-6.
19. Donovan DM, Foster-Frey J, Dong S, Rousseau GM, Moineau S, Pritchard DG. 2006. The cell lysis activity of the Streptococcus agalactiae bacteriophage B30 endolysin relies on the cysteine, histidine-dependent amidohydrolase/peptidase domain. Appl Environ Microbiol 72: 5108–5112. https://doi.org/10.1128/AEM.03065-05.
20. Gu J, Feng Y, Feng X, Sun C, Lei L, Ding W, Niu F, Jiao L, Yang M, Li Y, Liu X, Song J, Cui Z, Han D, Du C, Yang Y, Ouyang S, Liu ZJ, Han W. 2014. Structural and biochemical characterization reveals LysGH15 as an unprecedented “EF-hand-like” calcium-binding phage lysin. PLoS Pathog 10:e1004109. https://doi.org/10.1371/journal.ppat.1004109.
21. Sanz-Gaitero M, Keary R, Garcia-Doval C, Coffey A, van Raaij MJ. 2014. Crystal structure of the lytic CHAP(K) domain of the endolysin LysK from Staphylococcus aureus bacteriophage K. Virol J 11:133. https://doi.org/10.1186/1743-422X-11-133.
22. Horgan M, O’Flynn G, Garry J, Cooney J, Coffey A, Fitzgerald GF, Ross RP, McAuliffe O. 2009. Phage lysin LysK can be truncated to its CHAP domain and retain lytic activity against live antibiotic-resistant staphylococci. Appl Environ Microbiol 75:872– 874. https://doi.org/10.1128/AEM.01831-08.
23. Becker SC, Dong S, Baker JR, Foster-Frey J, Pritchard DG, Donovan DM. 2009. LysK CHAP endopeptidase domain is required for lysis of live staphylococcal cells. FEMS Microbiol Lett 294:52– 60. https://doi.org/10.1111/j.1574-6968.2009.01541.x.
24. Zhou Y, Zhang H, Bao H, Wang X, Wang R. 2017. The lytic activity of recombinant phage lysin LysKΔamidase against staphylococcal strains associated with bovine and human infections in the Jiangsu Province of China. Res Vet Sci 111:113–119. https://doi.org/10.1016/j.rvsc.2017.02.011.
25. Idelevich EA, von Eiff C, Friedrich AW, Iannelli D, Xia G, Peters G, Peschel A, Wanninger I, Becker K. 2011. In vitro activity against Staphylococcus aureus of a novel antimicrobial agent, PRF-119, a recombinant chimeric bacteriophage endolysin. Antimicrob Agents Chemother 55:4416–4419. https://doi.org/10.1128/AAC.00217-11.
26. Mao J, Schmelcher M, Harty WJ, Foster-Frey J, Donovan DM. 2013. Chimeric Ply187 endolysin kills Staphylococcus aureus more effectively than the parental enzyme. FEMS Microbiol Lett 342:30–36. https://doi.org/10.1111/1574-6968.12104.
27. Becker SC, Roach DR, Chauhan VS, Shen Y, Foster-Frey J, Powell AM, Bauchan G, Lease RA, Mohammadi H, Harty WJ, Simmons C, Schmelcher M, Camp M, Dong S, Baker JR, Sheen TR, Doran KS, Pritchard DG, Almeida RA, Nelson DC, Marriott I, Lee JC, Donovan DM. 2016. Triple-acting lytic enzyme treatment of drug-resistant and intracellular Staphylococcus aureus. Sci Rep 6:25063. https://doi.org/10.1038/srep25063.
28. Moormeier DE, Bayles KW. 2017. Staphylococcus aureus biofilm: a complex developmental organism. Mol Microbiol 104:365–376. https://doi.org/10.1111/mmi.13634.
29. Yang H, Zhang Y, Huang Y, Yu J, Wei H. 2014. Degradation of methicillin-resistant Staphylococcus aureus biofilms using a chimeric lysin. Biofoul-ing 30:667– 674. https://doi.org/10.1080/08927014.2014.905927.
30. Son JS, Lee SJ, Jun SY, Yoon SJ, Kang SH, Paik HR, Kang JO, Choi YJ. 2010. Antibacterial and biofilm removal activity of a Podoviridae Staphylococcus aureus bacteriophage SAP-2 and a derived recombinant cell-wall-degrading enzyme. Appl Microbiol Biotechnol 86:1439–1449. https://doi.org/10.1007/s00253-009-2386-9.
31. Sass P, Bierbaum G. 2007. Lytic activity of recombinant bacteriophage phi11 and phi12 endolysins on whole cells and biofilms of Staphylococcus aureus. Appl Environ Microbiol 73:347–352. https://doi.org/10.1128/AEM.01616-06.
32. Jun SY, Jung GM, Yoon SJ, Oh MD, Choi YJ, Lee WJ, Kong JC, Seol JG, Kang SH. 2013. Antibacterial properties of a pre-formulated recombinant phage endolysin, SAL-1. Int J Antimicrob Agents 41:156–161. https://doi.org/10.1016/j.ijantimicag.2012.10.011.
33. Fenton M, Keary R, McAuliffe O, Ross RP, O’Mahony J, Coffey A. 2013. Bacteriophage-derived peptidase CHAP(K) eliminates and prevents Staphylococcal biofilms. Int J Microbiol 2013:625341. https://doi.org/10.1155/2013/625341.
34. Linden SB, Zhang H, Heselpoth RD, Shen Y, Schmelcher M, Eichenseher F, Nelson DC. 2015. Biochemical and biophysical characterization of PlyGRCS, a bacteriophage endolysin active against methicillin-resistant Staphylococcus aureus. Appl Microbiol Biotechnol 99:741–752. https://doi.org/10.1007/s00253-014-5930-1.
35. Yang H, Zhang H, Wang J, Yu J, Wei H. 2017. A novel chimeric lysin with robust antibacterial activity against planktonic and biofilm methicillin-resistant Staphylococcus aureus. Sci Rep 7:40182. https://doi.org/10.1038/srep40182.
36. Gutiérrez D, Ruas-Madiedo P, Martínez B, Rodríguez A, García P. 2014. Effective removal of staphylococcal biofilms by the endolysin LysH5. PLoS One 9:e107307. https://doi.org/10.1371/journal.pone.0107307.
37. Chopra S, Harjai K, Chhibber S. 2015. Potential of sequential treatment with minocycline and S. aureus specific phage lysin in eradication of MRSA biofilms: an in vitro study. Appl Microbiol Biotechnol 99: 3201–3210. https://doi.org/10.1007/s00253-015-6460-1.
38. Gutiérrez D, Fernández L, Martínez B, Ruas-Madiedo P, García P, Rodríguez A. 2017. Real-time assessment of Staphylococcus aureus biofilm disruption by phage-derived proteins. Front Microbiol 8:1632. https://doi.org/10.3389/fmicb.2017.01632.
39. Solanki K, Grover N, Downs P, Paskaleva EE, Mehta KK, Lee L, Schadler LS, Kane RS, Dordick JS. 2013. Enzyme-based listericidal nanocomposites. Sci Rep 3:1584. https://doi.org/10.1038/srep01584.
40. Fischetti VA. 2006. Using phage lytic enzymes to control pathogenic bacteria. BMC Oral Health 6(Suppl 1):S16. https://doi.org/10.1186/1472 -6831-6-S1-S16.
41. Pastagia M, Euler C, Chahales P, Fuentes-Duculan J, Krueger JG, Fischetti VA. 2011. A novel chimeric lysin shows superiority to mupirocin for skin decolonization of methicillin-resistant and -sensitive Staphylococcus aureus strains. Antimicrob Agents Chemother 55:738–744. https://doi.org/10.1128/AAC.00890-10.
42. Rodríguez-Rubio L, Martínez B, Rodríguez A, Donovan DM, Götz F, García P. 2013. The phage lytic proteins from the Staphylococcus aureus bacteriophage vB_SauS-phiIPLA88 display multiple active catalytic domains and do not trigger staphylococcal resistance. PLoS One 8:e64671. https://doi.org/10.1371/journal.pone.0064671.
43. Fernández L, González S, Campelo AB, Martínez B, Rodríguez A, García P. 2017. Downregulation of autolysin-encoding genes by phage-derived lytic proteins inhibits biofilm formation in Staphylococcus aureus. Antimicrob Agents Chemother 61:e02724-16. https://doi.org/10.1128/AAC.02724-16.
44. Coates T, Bax R, Coates A. 2009. Nasal decolonization of Staphylococcus aureus with mupirocin: strengths, weaknesses and future prospects. J Antimicrob Chemother 64:9–15. https://doi.org/10.1093/jac/dkp159.
45. Paul VD, Rajagopalan SS, Sundarrajan S, George SE, Asrani JY, Pillai R, Chikkamadaiah R, Durgaiah M, Sriram B, Padmanabhan S. 2011. A novel bacteriophage tail-associated muralytic enzyme (TAME) from phage K and its development into a potent antistaphylococcal protein. BMC Microbiol 11:226. https://doi.org/10.1186/1471-2180-11-226.
46. Fenton M, Casey PG, Hill C, Gahan CG, Ross RP, McAuliffe O, O’Mahony J, Maher F, Coffey A. 2010. The truncated phage lysin CHAP(k) eliminates Staphylococcus aureus in the nares of mice. Bioeng Bugs 1:404– 407. https://doi.org/10.4161/bbug.1.6.13422.
47. 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 phi MR11. J Infect Dis 196: 1237–1247. https://doi.org/10.1086/521305.
48. Gu J, Xu W, Lei L, Huang J, Feng X, Sun C, Du C, Zuo J, Li Y, Du T, Li L, Han W. 2011. LysGH15, a novel bacteriophage lysin, protects a murine bacteremia model efficiently against lethal methicillin-resistant Staphylococcus aureus infection. J Clin Microbiol 49:111–117. https://doi.org/10.1128/JCM.01144-10.
49. Chopra S, Harjai K, Chhibber S. 2016. Potential of combination therapy of endolysin MR-10 and minocycline in treating MRSA induced systemic and localized burn wound infections in mice. Int J Med Microbiol 306:707–716. https://doi.org/10.1016/j.ijmm.2016.08.003.
50. Schmelcher M, Shen Y, Nelson DC, Eugster MR, Eichenseher F, Hanke DC, Loessner MJ, Dong S, Pritchard DG, Lee JC, Becker SC, Foster-Frey J, Donovan DM. 2015. Evolutionarily distinct bacteriophage endolysins featuring conserved peptidoglycan cleavage sites protect mice from MRSA infection. J Antimicrob Chemother 70:1453–1465. https://doi.org/10.1093/jac/dku552.
51. Gupta R, Prasad Y. 2011. P-27/HP endolysin as antibacterial agent for antibiotic resistant Staphylococcus aureus of human infections. Curr Microbiol. P-27 63:39– 45. https://doi.org/10.1007/s00284-011-9939-8.
52. Schmelcher M, Powell AM, Becker SC, Camp MJ, Donovan DM. 2012. Chimeric phage lysins act synergistically with lysostaphin to kill mastitis-causing Staphylococcus aureus in murine mammary glands. Appl Environ Microbiol 78:2297–2305. https://doi.org/10.1128/AEM.07050-11.
53. Fan J, Zeng Z, Mai K, Yang Y, Feng J, Bai Y, Sun B, Xie Q, Tong Y, Ma J. 2016. Preliminary treatment of bovine mastitis caused by Staphylococcus aureus, with trx-SA1, recombinant endolysin of S. aureus bacteriophage IME-SA1. Vet Microbiol 191:65–71. https://doi.org/10.1016/j.vetmic.2016.06.001.
54. Singh PK, Donovan DM, Kumar A. 2014. Intravitreal injection of the chimeric phage endolysin Ply187 protects mice from Staphylococcus aureus endophthalmitis. Antimicrob Agents Chemother 58:4621– 4629. https://doi.org/10.1128/AAC.00126-14.
55. Schuch R, Lee HM, Schneider BC, Sauve KL, Law C, Khan BK, Rotolo JA, Horiuchi Y, Couto DE, Raz A, Fischetti VA, Huang DB, Nowinski RC, Wittekind M. 2014. Combination therapy with lysin CF-301 and antibiotic is superior to antibiotic alone for treating methicillin-resistant Staphylococcus aureus-induced murine bacteremia. J Infect Dis 209:1469–1478. https://doi.org/10.1093/infdis/jit637.
56. Andrade EL, Bento AF, Cavalli J, Oliveira SK, Schwanke RC, Siqueira JM, Freitas CS, Marcon R, Calixto JB. 2016. Non-clinical studies in the process of new drug development—part II: good laboratory practice, metabolism, pharmacokinetics, safety and dose translation to clinical studies. Braz J Med Biol Res 49:e5646. https://doi.org/10.1590/1414 -431X20165646.
57. George SE, Chikkamadaiah R, Durgaiah M, Joshi AA, Thankappan UP, Madhusudhana SN, Sriram B. 2012. Biochemical characterization and evaluation of cytotoxicity of antistaphylococcal chimeric protein P128. BMC Res Notes 5:280. https://doi.org/10.1186/1756-0500-5-280.
58. Jun SY, Jung GM, Yoon SJ, Choi YJ, Koh WS, Moon KS, Kang SH. 2014. Preclinical safety evaluation of intravenously administered SAL200 containing the recombinant phage endolysin SAL-1 as a pharmaceutical ingredient. Antimicrob Agents Chemother 58:2084–2088. https://doi.org/10.1128/AAC.02232-13.
59. Jun SY, Jung GM, Yoon SJ, Youm SY, Han HY, Lee JH, Kang SH. 2016. Pharmacokinetics of the phage endolysin-based candidate drug SAL200 in monkeys and its appropriate intravenous dosing period. Clin Exp Pharmacol Physiol 43:1013–1016. https://doi.org/10.1111/1440-1681.12613.
60. Totté JEE, van Doorn MB, Pasmans SGMA. 2017. Successful treatment of chronic Staphylococcus aureus-related dermatoses with the topical endolysin Staphefekt SA.100: a report of 3 cases. Case Rep Dermatol 9:19–25. https://doi.org/10.1159/000473872.
61. Jun SY, Jang IJ, Yoon S, Jang K, Yu KS, Cho JY, Seong MW, Jung GM, Yoon SJ, Kang SH. 2017. Pharmacokinetics and tolerance of the phage endolysin-based candidate drug SAL200 after a single intravenous administration among healthy volunteers. Antimicrob Agents Chemother 61:e02629-16. https://doi.org/10.1128/AAC.02629-16.
62. Chang Y, Yoon H, Kang DH, Chang PS, Ryu S. 2017. Endolysin LysSA97 is synergistic with carvacrol in controlling Staphylococcus aureus in foods. Int J Food Microbiol 244:19–26. https://doi.org/10.1016/j.ijfoodmicro.2016.12.007.
63. García P, Martínez B, Rodríguez L, Rodríguez A. 2010. Synergy between the phage endolysin LysH5 and nisin to kill Staphylococcus aureus in pasteurized milk. Int J Food Microbiol 141:151–155. https://doi.org/10.1016/j.ijfoodmicro.2010.04.029.
64. Rodríguez-Rubio L, Martínez B, Donovan DM, García P, Rodríguez A. 2013. Potential of the virion-associated peptidoglycan hydrolase HydH5 and its derivative fusion proteins in milk biopreservation. PLoS One 8:e54828. https://doi.org/10.1371/journal.pone.0054828.
65. Obeso JM, Martínez B, Rodríguez A, García P. 2008. Lytic activity of the recombinant staphylococcal bacteriophage PhiH5 endolysin active against Staphylococcus aureus in milk. Int J Food Microbiol 128:212–218. https://doi.org/10.1016/j.ijfoodmicro.2008.08.010.
66. García P, Rodríguez L, Rodríguez A, Martínez B. 2010. Food biopreservation: promising strategies using bacteriocins, bacteriophages and endolysins. Trends Food Sci Technol 21:373–382. https://doi.org/10.1016/j.tifs.2010.04.010.
67. Guo T, Xin Y, Zhang C, Ouyang X, Kong J. 2016. The potential of the endolysin Lysdb from Lactobacillus delbrueckii phage for combating Staphylococcus aureus during cheese manufacture from raw milk. Appl Microbiol Biotechnol 100:3545–3554. https://doi.org/10.1007/s00253 -015-7185-x.
68. Yu J, Zhang Y, Zhang Y, Li H, Yang H, Wei H. 2016. Sensitive and rapid detection of Staphylococcus aureus in milk via cell binding domain of lysin. Biosens Bioelectron 77:366–371. https://doi.org/10.1016/j.bios.2015.09.058.
69. Rosano GL, Ceccarelli EA. 2014. Recombinant protein expression in Escherichia coli: advances and challenges. Front Microbiol 5:172. https://doi.org/10.3389/fmicb.2014.00172.
70. Adrio JL, Demain AL. 2010. Recombinant organisms for production of industrial products. Bioeng Bugs 1:116–131. https://doi.org/10.4161/bbug.1.2.10484.
71. Stoffels L, Taunt HN, Charalambous B, Purton S. 2017. Synthesis of bacteriophage lytic proteins against Streptococcus pneumoniae in the chloroplast of Chlamydomonas reinhardtii. Plant Biotechnol J 15: 1130–1140. https://doi.org/10.1111/pbi.12703.
72. Marin Viegas VS, Ocampo CG, Petruccelli S. 2017. Vacuolar deposition of recombinant proteins in plant vegetative organs as a strategy to increase yields. Bioengineered 8:203–211. https://doi.org/10.1080/21655979.2016.1222994.
73. Walsh G. 2014. Proteins: biochemistry and biotechnology, 2nd ed. John Wiley & Sons, Chichester, England.
74. Filatova LY, Donovan DM, Becker SC, Lebedev DN, Priyma AD, Koudria-chova HV, Kabanov AV, Klyachko NL. 2013. Physicochemical characterization of the staphylolytic LysK enzyme in complexes with polycationic polymers as a potent antimicrobial. Biochimie 95:1689–1696. https://doi.org/10.1016/j.biochi.2013.04.013.
75. Filatova LY, Donovan DM, Ishnazarova NT, Foster-Frey JA, Becker SC, Pugachev VG, Balabushevich NG, Dmitrieva NF, Klyachko NL. 2016. A chimeric LysK-lysostaphin fusion enzyme lysing Staphylococcus aureus cells: a study of both kinetics of inactivation and specifics of interaction with anionic polymers. Appl Biochem Biotechnol 180:544–557. https://doi.org/10.1007/s12010-016-2115-7.
76. Mura S, Nicolas J, Couvreur P. 2013. Stimuli-responsive nanocarriers for drug delivery. Nat Mater 12:991–1003. https://doi.org/10.1038/nmat3776.
77. Hathaway H, Ajuebor J, Stephens L, Coffey A, Potter U, Sutton JM, Jenkins AT. 2017. Thermally triggered release of the bacteriophage endolysin CHAPK and the bacteriocin lysostaphin for the control of methicillin resistant Staphylococcus aureus (MRSA). J Control Release 245:108–115. https://doi.org/10.1016/j.jconrel.2016.11.030.
78. European Commission. 2001. Medical devices: guidance document. Guidelines relating to the application of the Council Directive 90/385/ EEC on active implantable medical devices. European Commission, Brussels, Belgium. http://ec.europa.eu/consumers/sectors/medical-devices/files/meddev/2_1_3____07-2001_en.pdf. Accessed April 2017.
79. Cooper CJ, Khan Mirzaei M, Nilsson AS. 2016. Adapting drug approval pathways for bacteriophage-based therapeutics. Front Microbiol 7:1209. https://doi.org/10.3389/fmicb.2016.01209.
80. Verbeken G, Pirnay JP, De Vos D, Jennes S, Zizi M, Lavigne R, Casteels M, Huys I. 2012. Optimizing the European regulatory framework for sustainable bacteriophage therapy in human medicine. Arch Immunol Ther Exp 60:161–172. https://doi.org/10.1007/s00005-012-0175-0.
81. Kinch MS. 2015. An overview of FDA-approved biologics medicines. Drug Discov Today 20:393–398. https://doi.org/10.1016/j.drudis.2014.09.003.
82. Meekings KN, Williams CS, Arrowsmith JE. 2012. Orphan drug development: an economically viable strategy for biopharma R&D. Drug Discov Today 17:660– 664. https://doi.org/10.1016/j.drudis.2012.02.005.
83. Tufts Center for the Study of Drug Development. 18 November 2014. Cost to develop and win marketing approval for a new drug is $2.6 billion. News of the Tufts Center for the Study of Drug Development, Boston, MA. http://csdd.tufts.edu/news/complete_story/pr_tufts_csdd _2014_cost_study. Accessed April 2017.
84. The European Parliament and the Council of the European Union. 2001. Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use. Off J Eur Union L 311/67–L 311/128. https://ec.europa.eu/health//sites/health/files/files/eudralex/vol-1/dir_2001_83 _cons2009/2001_83_cons2009_en.pdf.
85. The European Parliament and the Council of the European Union. 2004. Regulation (EC) no 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorization and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency. Off J Eur Union L 136/1–L 136/33. http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri
86. The European Parliament and the Council of the European Union. 2008. Regulation (EC) no 1333/2008 of the European Parliament and of the Council of 16 December 2008 on food additives. Off J Eur Union L 354, 31.12.2008. https://www.fsai.ie/uploadedFiles/Consol _Reg1333_2008.pdf.
87. European Chemicals Agency. 2008. BPR legislation. ECHA, Helsinki, Finland. https://echa.europa.eu/regulations/biocidal-products-regulation/legislation.
88. US Congress. 1910. Federal Insecticide, Fungicide, and Rodenticide Act. 36 Stat 331. US Congress, Washington, DC.
89. US Congress. 1966. Medical device amendments of 1966. Public law 94-295. US Congress, Washington, DC. https://www.gpo.gov/fdsys/pkg/STATUTE-90/pdf/STATUTE-90-Pg539.pdf.
90. U.S. Congress. 1938. Federal Food, Drug, and Cosmetic Act (FD&C Act). 21 USC, chapter 9. US Congress, Washington, DC. https://www.fda.gov/RegulatoryInformation/LawsEnforcedbyFDA/FederalFoodDrugand CosmeticActFDCAct/default.htm.
91. Rodríguez-Rubio L, Martínez B, Rodríguez A, Donovan DM, García P. 2012. Enhanced staphylolytic activity of the Staphylococcus aureus bacteriophage vB_SauS-phiIPLA88 HydH5 virion-associated peptidoglycan hydrolase: fusions, deletions, and synergy with LysH5. Appl Environ Microbiol 78:2241–2248. https://doi.org/10.1128/AEM.07621-11.