Beyond traditional antimicrobials: A Caenorhabditis elegans model for discovery of novel anti-infectives

Frontiers in Microbiology

Volumn 7, Issue DEC, 2016, Pages

  Kong, Cin ^a,b   Eng, Su Anne ^a   Lim, Mei Perng ^a   Nathan, Sheila ^a  

^a UNIVERSITI KEBANGSAAN MALAYSIA   (Malaysia)

^b UNIVERSITY OF NOTTINGHAM MALAYSIA CAMPUS   (Malaysia)

Author keywords

Anti virulence; Antimicrobial peptides; Antimicrobials; Caenorhabditis elegans; Immunomodulator

Indexed keywords

ANTIINFECTIVE AGENT; LYSOZYME;

ANTIBIOTIC RESISTANCE; ANTIMICROBIAL ACTIVITY; BACTERIAL LOAD; BACTERIAL VIABILITY; BACTERIAL VIRULENCE; CAENORHABDITIS ELEGANS; ENTEROCOCCUS FAECALIS; GENE SILENCING; IMMUNE RESPONSE; METHICILLIN RESISTANT STAPHYLOCOCCUS AUREUS; MINIMUM INHIBITORY CONCENTRATION; NONHUMAN; REVIEW;

EID: 85009164770     PISSN: None     EISSN: 1664302X     Source Type: Journal    
DOI: 10.3389/fmicb.2016.01956     Document Type: Review

References (133)

1. Aballay, A., Yorgey, P., and Ausubel, F. M. (2000). Salmonella typhimurium proliferates and establishes a persistent infection in the intestine of Caenorhabditis elegans. Curr. Biol. 10, 1539-1542. doi: 10.1016/S0960-9822(00)00830-7
2. Adonizio, A., Kong, K. F., and Mathee, K. (2008a). Inhibition of quorum sensing-controlled virulence factor production in Pseudomonas aeruginosa by South Florida plant extracts. Antimicrob. Agents Chemother. 52, 198-203. doi: 10.1128/AAC.00612-07
3. Adonizio, A., Leal, S. M. Jr., Ausubel, F. M., and Mathee, K. (2008b). Attenuation of Pseudomonas aeruginosa virulence by medicinal plants in a Caenorhabditis elegans model system. J. Med. Microbiol. 57, 809-813. doi: 10.1099/jmm.0.47802-0
4. Afacan, N. J., Yeung, A. T., Pena, O. M., and Hancock, R. E. (2012). Therapeutic potential of host defense peptides in antibiotic-resistant infections. Curr. Pharm. Des. 18, 807-819. doi: 10.2174/138161212799277617
5. Alegado, R. A., Campbell, M. C., Chen, W. C., Slutz, S. S., and Tan, M. W. (2003). Characterization of mediators of microbial virulence and innate immunity using the Caenorhabditis elegans host-pathogen model. Cell. Microbiol. 5, 435-444. doi: 10.1046/j.1462-5822.2003.00287.x
6. Allen, R. C., Popat, R., Diggle, S. P., and Brown, S. P. (2014). Targeting virulence: can we make evolution-proof drugs? Nat. Rev. Microbiol. 12, 300-308. doi: 10.1038/nrmicro3232
7. Alper, S., Mcbride, S. J., Lackford, B., Freedman, J. H., and Schwartz, D. A. (2007). Specificity and complexity of the Caenorhabditis elegans innate immune response. Mol. Cell. Biol. 27, 5544-5553. doi: 10.1128/MCB.02070-06
8. Alshawsh, M. A., Abdulla, M. A., Ismail, S., Amin, Z. A., Qader, S. W., Hadi, H. A., et al. (2012). Free radical scavenging, antimicrobial and immunomodulatory activities of Orthosiphon stamineus. Molecules 17, 5385-5395. doi: 10.3390/molecules17055385
9. Antoshechkin, I., and Sternberg, P. W. (2007). The versatile worm: genetic and genomic resources for Caenorhabditis elegans research. Nat. Rev. Genet. 8, 518-532. doi: 10.1038/nrg2105
10. Arvanitis, M., Glavis-Bloom, J., and Mylonakis, E. (2013). C. elegans for anti-infective discovery. Curr. Opin. Pharm. 13, 769-774. doi: 10.1016/j.coph.2013.08.002
11. Bakkiyaraj, D., and Pandian, S. K. (2010). In vitro and in vivo antibiofilm activity of a coral associated actinomycete against drug resistant Staphylococcus aureus biofilms. Biofouling 26, 711-717. doi: 10.1080/08927014.2010.511200
12. Banyai, L., and Patthy, L. (1998). Amoebapore homologs of Caenorhabditis elegans. Biochim. Biophys. Acta 1429, 259-264. doi: 10.1016/S0167-4838(98)00237-4
13. Bjarnsholt, T., Jensen, P. O., Rasmussen, T. B., Christophersen, L., Calum, H., Hentzer, M., et al. (2005). Garlic blocks quorum sensing and promotes rapid clearing of pulmonary Pseudomonas aeruginosa infections. Microbiology 151, 3873-3880. doi: 10.1099/mic.0.27955-0
14. Boucher, H. W., Talbot, G. H., Benjamin, D. K. Jr., Bradley, J., Guidos, R. J., Jones, R. N., et al. (2013). 10 x '20 Progress-development of new drugs active against gram-negative bacilli: an update from the Infectious Diseases Society of America. Clin. Infect. Dis. 56, 1685-1694. doi: 10.1093/cid/cit152
15. Brackman, G., Breyne, K., De Rycke, R., Vermote, A., Van Nieuwerburgh, F., Meyer, E., et al. (2016). The quorum sensing inhibitor hamamelitannin increases antibiotic susceptibility of Staphylococcus aureus biofilms by affecting peptidoglycan biosynthesis and eDNA release. Sci. Rep. 6:20321. doi: 10.1038/srep20321
16. Briers, Y., Walmagh, M., Van Puyenbroeck, V., Cornelissen, A., Cenens, W., Aertsen, A., et al. (2014). Engineered endolysin-based "Artilysins" to combat multidrug-resistant gram-negative pathogens. MBio 5:e01379-14. doi: 10.1128/mBio.01379-14
17. Brown, E. D., and Wright, G. D. (2016). Antibacterial drug discovery in the resistance era. Nature 529, 336-343. doi: 10.1038/nature17042
18. Bruhn, H. (2005). A short guided tour through functional and structural features of saposin-like proteins. Biochem. J. 389, 249-257. doi: 10.1042/BJ20050051
19. Cai, Y., Cao, X., and Aballay, A. (2014). Whole-animal chemical screen identifies colistin as a new immunomodulator that targets conserved pathways. MBio 5:e01235-14. doi: 10.1128/mBio.01235-14
20. Cho, H. S., Lee, J. H., Cho, M. H., and Lee, J. (2015). Red wines and flavonoids diminish Staphylococcus aureus virulence with anti-biofilm and anti-hemolytic activities. Biofouling 31, 1-11. doi: 10.1080/08927014.2014.991319
21. Choi, E. J., Kim, H. I., Kim, J. A., Jun, S. Y., Kang, S. H., Park, D. J., et al. (2015). The herbal-derived honokiol and magnolol enhances immune response to infection with methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA). Appl. Microbiol. Biotechnol. 99, 4387-4396. doi: 10.1007/s00253-015-6382-y
22. Cohen, L. B., and Troemel, E. R. (2015). Microbial pathogenesis and host defense in the nematode C. elegans. Curr. Opin. Microbiol. 23, 94-101. doi: 10.1016/j.mib.2014.11.009
23. Conery, A. L., Larkins-Ford, J., Ausubel, F. M., and Kirienko, N. V. (2014). High-throughput screening for novel anti-infectives using a C. elegans pathogenesis model. Curr. Protoc. Chem. Biol. 6, 25-37. doi: 10.1002/9780470559277.ch130160
24. Couillault, C., Pujol, N., Reboul, J., Sabatier, L., Guichou, J. F., Kohara, Y., et al. (2004). TLR-independent control of innate immunity in Caenorhabditis elegans by the TIR domain adaptor protein TIR-1, an ortholog of human SARM. Nat. Immunol. 5, 488-494. doi: 10.1038/ni1060
25. Desalermos, A., Muhammed, M., Glavis-Bloom, J., and Mylonakis, E. (2011). Using C. elegans for antimicrobial drug discovery. Exp. Opin. Drug Discov. 6, 645-652. doi: 10.1517/17460441.2011.573781
26. Dharmalingam, K., Tan, B. K., Mahmud, M. Z., Sedek, S. A., Majid, M. I., Kuah, M. K., et al. (2012). Swietenia macrophylla extract promotes the ability of Caenorhabditis elegans to survive Pseudomonas aeruginosa infection. J. Ethnopharmacol. 139, 657-663. doi: 10.1016/j.jep.2011.12.016
27. Dinh, J., Angeloni, J. T., Pederson, D. B., Wang, X., Cao, M., and Dong, Y. (2014). Cranberry extract standardized for proanthocyanidins promotes the immune response of Caenorhabditis elegans to Vibrio cholerae through the p38 MAPK pathway and HSF-1. PLoS ONE 9:e103290. doi: 10.1371/journal.pone.0103290
28. Dolla, N. K., Chen, C., Larkins-Ford, J., Rajamuthiah, R., Jagadeesan, S., Conery, A. L., et al. (2015). On the mechanism of Berberine-INF55 (5-Nitro-2-phenylindole) hybrid qntibacterials. Aust. J. Chem. 67, 1471-1480. doi: 10.1071/CH14426
29. Durai, S., Vigneshwari, L., and Balamurugan, K. (2013). Caenorhabditis elegans-based in vivo screening of bioactives from marine sponge-associated bacteria against Vibrio alginolyticus. J. Appl. Microbiol. 115, 1329-1342. doi: 10.1111/jam.12335
30. Eng, S. A., and Nathan, S. (2015). Curcumin rescues Caenorhabditis elegans from a Burkholderia pseudomallei infection. Front. Microbiol. 6:290. doi: 10.3389/fmicb.2015.00290
31. Ermolaeva, M. A., and Schumacher, B. (2014). Insights from the worm: the C. elegans model for innate immunity. Semin. Immunol. 26, 303-309. doi: 10.1016/j.smim.2014.04.005
32. Ewbank, J. J., and Zugasti, O. (2011). C. elegans: model host and tool for antimicrobial drug discovery. Dis. Model. Mech. 4, 300-304. doi: 10.1242/dmm.006684
33. Fekete, C., Tholander, M., Rajashekar, B., Ahren, D., Friman, E., Johansson, T., et al. (2008). Paralysis of nematodes: shifts in the transcriptome of the nematode-trapping fungus Monacrosporium haptotylum during infection of Caenorhabditis elegans. Environ. Microbiol. 10, 364-375. doi: 10.1111/j.1462-2920.2007.01457.x
34. Fuchs, B. B., Rajamuthiah, R., Souza, A. C., Eatemadpour, S., Rossoni, R. D., Santos, D. A., et al. (2016). Inhibition of bacterial and fungal pathogens by the orphaned drug auranofin. Future Med. Chem. 8, 117-132. doi: 10.4155/fmc.15.182
35. Garsin, D. A., Sifri, C. D., Mylonakis, E., Qin, X., Singh, K. V., Murray, B. E., et al. (2001). A simple model host for identifying Gram-positive virulence factors. Proc. Natl. Acad. Sci. U.S.A. 98, 10892-10897. doi: 10.1073/pnas.191378698
36. Garsin, D. A., Villanueva, J. M., Begun, J., Kim, D. H., Sifri, C. D., Calderwood, S. B., et al. (2003). Long-lived C. elegans daf-2 mutants are resistant to bacterial pathogens. Science 300:1921. doi: 10.1126/science.1080147
37. Gravato-Nobre, M. J., Vaz, F., Filipe, S., Chalmers, R., and Hodgkin, J. (2016). The invertebrate lysozyme effector ILYS-3 is systemically activated in response to danger signals and confers antimicrobial protection in C. elegans. PLoS Pathog. 12:e1005826. doi: 10.1371/journal.ppat.1005826
38. Harjai, K., Kumar, R., and Singh, S. (2010). Garlic blocks quorum sensing and attenuates the virulence of Pseudomonas aeruginosa. FEMS Immunol. Med. Microbiol. 58, 161-168. doi: 10.1111/j.1574-695X.2009.00614.x
39. Ho Sui, S. J., Lo, R., Fernandes, A. R., Caulfield, M. D., Lerman, J. A., Xie, L., et al. (2012). Raloxifene attenuates Pseudomonas aeruginosa pyocyanin production and virulence. Int. J. Antimicrob. Agents 40, 246-251. doi: 10.1016/j.ijantimicag.2012.05.009
40. Hodgkin, J., Felix, M. A., Clark, L. C., Stroud, D., and Gravato-Nobre, M. J. (2013). Two leucobacter strains exert complementary virulence on Caenorhabditis including death by worm-star formation. Curr. Biol. 23, 2157-2161. doi: 10.1016/j.cub.2013.08.060
41. Hodgkin, J., Kuwabara, P. E., and Corneliussen, B. (2000). A novel bacterial pathogen, Microbacterium nematophilum, induces morphological change in the nematode C. elegans. Curr. Biol. 10, 1615-1618. doi: 10.1016/S0960-9822(00)00867-8
42. Hoeckendorf, A., and Leippe, M. (2012). SPP-3, a saposin-like protein of Caenorhabditis elegans, displays antimicrobial and pore-forming activity and is located in the intestine and in one head neuron. Dev. Comp. Immunol. 38, 181-186. doi: 10.1016/j.dci.2012.05.007
43. Hoeckendorf, A., Stanisak, M., and Leippe, M. (2012). The saposin-like protein SPP-12 is an antimicrobial polypeptide in the pharyngeal neurons of Caenorhabditis elegans and participates in defence against a natural bacterial pathogen. Biochem. J. 445, 205-212. doi: 10.1042/BJ20112102
44. Hom, K., Heinzl, G. A., Eakanunkul, S., Lopes, P. E., Xue, F., Mackerell, A. D. Jr., et al. (2013). Small molecule antivirulents targeting the iron-regulated heme oxygenase (HemO) of P. aeruginosa. J. Med. Chem. 56, 2097-2109. doi: 10.1021/jm301819k
45. Husain, F. M., Ahmad, I., Asif, M., and Tahseen, Q. (2013). Influence of clove oil on certain quorum-sensing-regulated functions and biofilm of Pseudomonas aeruginosa and Aeromonas hydrophila. J. Biosci. (Bangalore) 38, 835-844. doi: 10.1007/s12038-013-9385-9
46. Husain, F. M., Ahmad, I., Khan, M. S., Ahmad, E., Tahseen, Q., and Alshabib, N. A. (2015a). Sub-MICs of Mentha piperita essential oil and menthol inhibits AHL mediated quorum sensing and biofilm of Gram-negative bacteria. Front. Microbiol. 6:420. doi: 10.3389/fmicb.2015.00420
47. Husain, F. M., Ahmad, I., Khan, M. S., and Al-Shabib, N. A. (2015b). Trigonella foenum-graceum (Seed) extract interferes with quorum sensing regulated traits and biofilm formation in the strains of Pseudomonas aeruginosa and Aeromonas hydrophila. Evid. Based Complement. Alternat. Med. 2015:879540. doi: 10.1155/2015/879540
48. Imperi, F., Massai, F., Facchini, M., Frangipani, E., Visaggio, D., Leoni, L., et al. (2013). Repurposing the antimycotic drug flucytosine for suppression of Pseudomonas aeruginosa pathogenicity. Proc. Natl. Acad. Sci. U.S.A. 110, 7458-7463. doi: 10.1073/pnas.1222706110
49. Irazoqui, J. E., Troemel, E. R., Feinbaum, R. L., Luhachack, L. G., Cezairliyan, B. O., and Ausubel, F. M. (2010). Distinct pathogenesis and host responses during infection of C. elegans by P. aeruginosa and S. aureus. PLoS Pathog. 6:e1000982. doi: 10.1371/journal.ppat.1000982
50. Jakobsen, H., Bojer, M. S., Marinus, M. G., Xu, T., Struve, C., Krogfelt, K. A., et al. (2013). The alkaloid compound harmane increases the lifespan of Caenorhabditis elegans during bacterial infection, by modulating the nematode's innate immune response. PLoS ONE 8:e60519. doi: 10.1371/journal.pone.0060519
51. Jansson, H. B. (1994). Adhesion of conidia of Drechmeria coniospora to Caenorhabditis elegans wild type and mutants. J. Nematol. 26, 430-435.
52. Jayamani, E., Rajamuthiah, R., Larkins-Ford, J., Fuchs, B. B., Conery, A. L., Vilcinskas, A., et al. (2015). Insect-derived cecropins display activity against Acinetobacter baumannii in a whole-animal high-throughput Caenorhabditis elegans model. Antimicrob. Agents Chemother. 59, 1728-1737. doi: 10.1128/AAC.04198-14
53. Junker, L. M., and Clardy, J. (2007). High-throughput screens for small-molecule inhibitors of Pseudomonas aeruginosa biofilm development. Antimicrob. Agents Chemother. 51, 3582-3590. doi: 10.1128/AAC.00506-07
54. Kamath, R. S., and Ahringer, J. (2003). Genome-wide RNAi screening in Caenorhabditis elegans. Methods 30, 313-321. doi: 10.1016/S1046-2023(03)00050-1
55. Kandasamy, S., Khan, W., Evans, F., Critchley, A. T., and Prithiviraj, B. (2012). Tasco(R): a product of Ascophyllum nodosum enhances immune response of Caenorhabditis elegans against Pseudomonas aeruginosa infection. Mar. Drugs 10, 84-105. doi: 10.3390/md10010084
56. Kato, Y., Aizawa, T., Hoshino, H., Kawano, K., Nitta, K., and Zhang, H. (2002). abf-1 and abf-2, ASABF-type antimicrobial peptide genes in Caenorhabditis elegans. Biochem. J. 361, 221-230. doi: 10.1042/bj3610221
57. Kato, Y., and Komatsu, S. (1996). ASABF, a novel cysteine-rich antibacterial peptide isolated from the nematode Ascaris suum. Purification, primary structure, and molecular cloning of cDNA. J. Biol. Chem. 271, 30493-30498. doi: 10.1074/jbc.271.48.30493
58. Kim, H. I., Kim, J. A., Choi, E. J., Harris, J. B., Jeong, S. Y., Son, S. J., et al. (2015). In vitro and in vivo antimicrobial efficacy of natural plant-derived compounds against Vibrio cholerae of O1 El Tor Inaba serotype. Biosci. Biotechnol. Biochem. 79, 475-483. doi: 10.1080/09168451.2014.991685
59. Kim, W., Conery, A. L., Rajamuthiah, R., Fuchs, B. B., Ausubel, F. M., and Mylonakis, E. (2015). Identification of an antimicrobial agent effective against methicillin-resistant Staphylococcus aureus persisters using a fluorescence-based screening strategy. PLoS ONE 10:e0127640. doi: 10.1371/journal.pone.0127640
60. Kirienko, D. R., Revtovich, A. V., and Kirienko, N. V. (2016). A high-content, phenotypic screen identifies fluorouridine as an inhibitor of pyoverdine biosynthesis and Pseudomonas aeruginosa virulence. mSphere 1, e217-16. doi: 10.1128/mSphere.00217-16
61. Kirienko, N. V., Kirienko, D. R., Larkins-Ford, J., Wahlby, C., Ruvkun, G., and Ausubel, F. M. (2013). Pseudomonas aeruginosa disrupts Caenorhabditis elegans iron homeostasis, causing a hypoxic response and death. Cell Host Microbe 13, 406-416. doi: 10.1016/j.chom.2013.03.003
62. Kong, C., Tan, M. W., and Nathan, S. (2014a). Orthosiphon stamineus protects Caenorhabditis elegans against Staphylococcus aureus infection through immunomodulation. Biol Open 3, 644-655. doi: 10.1242/bio.20148334
63. Kong, C., Yehye, W. A., Abd Rahman, N., Tan, M. W., and Nathan, S. (2014b). Discovery of potential anti-infectives against Staphylococcus aureus using a Caenorhabditis elegans infection model. BMC Complement. Altern. Med. 14:4. doi: 10.1186/1472-6882-14-4
64. Kulshreshtha, G., Borza, T., Rathgeber, B., Stratton, G. S., Thomas, N. A., Critchley, A., et al. (2016). Red seaweeds Sarcodiotheca gaudichaudii and Chondrus crispus down-regulate virulence factors of Salmonella enteritidis and induce immune responses in Caenorhabditis elegans. Front. Microbiol. 7:421. doi: 10.3389/fmicb.2016.00421
65. Kumarasamy, K. K., Toleman, M. A., Walsh, T. R., Bagaria, J., Butt, F., Balakrishnan, R., et al. (2010). Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study. Lancet Infect. Dis. 10, 597-602. doi: 10.1016/S1473-3099(10)70143-2
66. Lai, Y., and Gallo, R. L. (2009). AMPed up immunity: how antimicrobial peptides have multiple roles in immune defense. Trends Immunol. 30, 131-141. doi: 10.1016/j.it.2008.12.003
67. Lakshmanan, U., Yap, A., Fulwood, J., Yichun, L., Hoon, S. S., Lim, J., et al. (2014). Establishment of a novel whole animal HTS technology platform for melioidosis drug discovery. Comb. Chem. High Throughput Screen 17, 790-803. doi: 10.2174/1386207317666141019195031
68. Lavigne, J. P., Bourg, G., Combescure, C., Botto, H., and Sotto, A. (2008). In-vitro and in-vivo evidence of dose-dependent decrease of uropathogenic Escherichia coli virulence after consumption of commercial Vaccinium macrocarpon (cranberry) capsules. Clin. Microbiol. Infect. 14, 350-355. doi: 10.1111/j.1469-0691.2007.01917.x
69. Lee, J. H., Kim, Y. G., Cho, H. S., Ryu, S. Y., Cho, M. H., and Lee, J. (2014). Coumarins reduce biofilm formation and the virulence of Escherichia coli O157:H7. Phytomedicine 21, 1037-1042. doi: 10.1016/j.phymed.2014.04.008
70. Lee, K., Lee, J. H., Kim, S. I., Cho, M. H., and Lee, J. (2014a). Anti-biofilm, anti-hemolysis, and anti-virulence activities of black pepper, cananga, myrrh oils, and nerolidol against Staphylococcus aureus. Appl. Microbiol. Biotechnol. 98, 9447-9457. doi: 10.1007/s00253-014-5903-4
71. Lee, K., Lee, J. H., Ryu, S. Y., Cho, M. H., and Lee, J. (2014b). Stilbenes reduce Staphylococcus aureus hemolysis, biofilm formation, and virulence. Foodborne Pathog. Dis. 11, 710-717. doi: 10.1089/fpd.2014.1758
72. Lee, K. M., Lim, J., Nam, S., Yoon, M. Y., Kwon, Y. K., Jung, B. Y., et al. (2011). Inhibitory effects of broccoli extract on Escherichia coli O157:H7 quorum sensing and in vivo virulence. FEMS Microbiol. Lett. 321, 67-74. doi: 10.1111/j.1574-6968.2011.02311.x
73. Li, W. H., Chang, C. H., Huang, C. W., Wei, C. C., and Liao, V. H. (2014). Selenite enhances immune response against Pseudomonas aeruginosa PA14 via SKN-1 in Caenorhabditis elegans. PLoS ONE 9:e105810. doi: 10.1371/journal.pone.0105810
74. Lim, M.-P., Firdaus-Raih, M., and Nathan, S. (2016). Nematode peptides with host-directed anti-inflammatory activity rescue Caenorhabditis elegans from a Burkholderia pseudomallei infection. Front. Microbiol. 7:1436. doi: 10.3389/fmicb.2016.01436
75. Liu, J., Hafting, J., Critchley, A. T., Banskota, A. H., and Prithiviraj, B. (2013). Components of the cultivated red seaweed Chondrus crispus enhance the immune response of Caenorhabditis elegans to Pseudomonas aeruginosa through the pmk-1, daf-2/daf-16, and skn-1 pathways. Appl. Environ. Microbiol. 79, 7343-7350. doi: 10.1128/AEM.01927-13
76. Liu, Y. Y., Wang, Y., Walsh, T. R., Yi, L. X., Zhang, R., Spencer, J., et al. (2016). Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect. Dis. 16, 161-168. doi: 10.1016/S1473-3099(15)00424-7
77. Luo, M., Shao, B., Nie, W., Wei, X. W., Li, Y. L., Wang, B. L., et al. (2015). Antitumor and adjuvant activity of lambda-carrageenan by stimulating immune response in cancer immunotherapy. Sci. Rep. 5:11062. doi: 10.1038/srep11062
78. Mallo, G. V., Kurz, C. L., Couillault, C., Pujol, N., Granjeaud, S., Kohara, Y., et al. (2002). Inducible antibacterial defense system in C. elegans. Curr. Biol. 12, 1209-1214. doi: 10.1016/S0960-9822(02)00928-4
79. Marsh, E. K., and May, R. C. (2012). Caenorhabditis elegans, a model organism for investigating immunity. Appl. Environ. Microbiol. 78, 2075-2081. doi: 10.1128/AEM.07486-11
80. McGann, P., Snesrud, E., Maybank, R., Corey, B., Ong, A. C., Clifford, R., et al. (2016). Escherichia coli harboring mcr-1 and blaCTX-M on a novel IncF plasmid: first report of mcr-1 in the United States. Antimicrob. Agents Chemother. 60, 4420-4421. doi: 10.1128/AAC.01103-16
81. Means, T. K., Mylonakis, E., Tampakakis, E., Colvin, R. A., Seung, E., Puckett, L., et al. (2009). Evolutionarily conserved recognition and innate immunity to fungal pathogens by the scavenger receptors SCARF1 and CD36. J. Exp. Med. 206, 637-653. doi: 10.1084/jem.20082109
82. Moy, T. I., Ball, A. R., Anklesaria, Z., Casadei, G., Lewis, K., and Ausubel, F. M. (2006). Identification of novel antimicrobials using a live-animal infection model. Proc. Natl. Acad. Sci. U.S.A. 103, 10414-10419. doi: 10.1073/pnas.0604055103
83. Moy, T. I., Conery, A. L., Larkins-Ford, J., Wu, G., Mazitschek, R., Casadei, G., et al. (2009). High-throughput screen for novel antimicrobials using a whole animal infection model. ACS Chem. Biol. 4, 527-533. doi: 10.1021/cb900084v
84. Musthafa, K. S., Balamurugan, K., Pandian, S. K., and Ravi, A. V. (2012a). 2, 5-Piperazinedione inhibits quorum sensing-dependent factor production in Pseudomonas aeruginosa PAO1. J. Basic Microbiol. 52, 679-686. doi: 10.1002/jobm.201100292
85. Musthafa, K. S., Sivamaruthi, B. S., Pandian, S. K., and Ravi, A. V. (2012b). Quorum sensing inhibition in Pseudomonas aeruginosa PAO1 by antagonistic compound phenylacetic acid. Curr. Microbiol. 65, 475-480. doi: 10.1007/s00284-012-0181-9
86. Mysliwy, J., Dingley, A. J., Stanisak, M., Jung, S., Lorenzen, I., Roeder, T., et al. (2010). Caenopore-5: the three-dimensional structure of an antimicrobial protein from Caenorhabditis elegans. Dev. Comp. Immunol. 34, 323-330. doi: 10.1016/j.dci.2009.11.003
87. Nathoo, A. N., Moeller, R. A., Westlund, B. A., and Hart, A. C. (2001). Identification of neuropeptide-like protein gene families in Caenorhabditis elegans and other species. Proc. Natl. Acad. Sci. U.S.A. 98, 14000-14005. doi: 10.1073/pnas.241231298
88. Nijnik, A. (2013). Immunomodulatory approaches for prevention and treatment of infectious diseases. Curr. Opin. Microbiol. 16, 590-595. doi: 10.1016/j.mib.2013.06.011
89. Nijnik, A., and Hancock, R. (2009). Host defence peptides: antimicrobial and immunomodulatory activity and potential applications for tackling antibiotic-resistant infections. Emerg. Health Threats J. 2, e1. doi: 10.3134/ehtj.09.001
90. O'Loughlin, C. T., Miller, L. C., Siryaporn, A., Drescher, K., Semmelhack, M. F., and Bassler, B. L. (2013). A quorum-sensing inhibitor blocks Pseudomonas aeruginosa virulence and biofilm formation. Proc. Natl. Acad. Sci. U.S.A. 110, 17981-17986. doi: 10.1073/pnas.1316981110
91. O'Reilly, L. P., Luke, C. J., Perlmutter, D. H., Silverman, G. A., and Pak, S. C. (2014). C. elegans in high-throughput drug discovery. Adv. Drug Del. Rev. 6, 247-253. doi: 10.1016/j.addr.2013.12.001
92. O'Rourke, D., Baban, D., Demidova, M., Mott, R., and Hodgkin, J. (2006). Genomic clusters, putative pathogen recognition molecules, and antimicrobial genes are induced by infection of C. elegans with M. nematophilum. Genome Res. 16, 1005-1016. doi: 10.1101/gr.50823006
93. Pendleton, J. N., Gorman, S. P., and Gilmore, B. F. (2013). Clinical relevance of the ESKAPE pathogens. Expert Rev. Anti Infect. Ther. 11, 297-308. doi: 10.1586/eri.13.12
94. Peschel, A., and Sahl, H. G. (2006). The co-evolution of host cationic antimicrobial peptides and microbial resistance. Nat. Rev. Microbiol. 4, 529-536. doi: 10.1038/nrmicro1441
95. Prithiviraj, B., Bais, H. P., Weir, T., Suresh, B., Najarro, E. H., Dayakar, B. V., et al. (2005). Down regulation of virulence factors of Pseudomonas aeruginosa by salicylic acid attenuates its virulence on Arabidopsis thaliana and Caenorhabditis elegans. Infect. Immun. 73, 5319-5328. doi: 10.1128/IAI.73.9.5319-5328.2005
96. Pujol, N., Zugasti, O., Wong, D., Couillault, C., Kurz, C. L., Schulenburg, H., et al. (2008). Anti-fungal innate immunity in C. elegans is enhanced by evolutionary diversification of antimicrobial peptides. PLoS Pathog. 4:e1000105. doi: 10.1371/journal.ppat.1000105
97. Pukkila-Worley, R., Feinbaum, R., Kirienko, N. V., Larkins-Ford, J., Conery, A. L., and Ausubel, F. M. (2012). Stimulation of host immune defenses by a small molecule protects C. elegans from bacterial infection. PLoS Genet. 8:e1002733. doi: 10.1371/journal.pgen.1002733
98. Rajalaxmi, M., Beema Shafreen, R., Iyer, P. M., Sahaya Vino, R., Balamurugan, K., and Pandian, S. K. (2016). An in silico, in vitro and in vivo investigation of indole-3-carboxaldehyde identified from the seawater bacterium Marinomonas sp. as an anti-biofilm agent against Vibrio cholerae O1. Biofouling 32, 1-12. doi: 10.1080/08927014.2016.1154545
99. Rajamuthiah, R., Fuchs, B. B., Jayamani, E., Kim, Y., Larkins-Ford, J., Conery, A., et al. (2014). Whole animal automated platform for drug discovery against multi-drug resistant Staphylococcus aureus. PLoS ONE 9:e89189. doi: 10.1371/journal.pone.0089189
100. Rajamuthiah, R., Jayamani, E., Majed, H., Conery, A. L., Kim, W., Kwon, B., et al. (2015). Antibacterial properties of 3-(phenylsulfonyl)-2-pyrazinecarbonitrile. Bioorg. Med. Chem. Lett. 25, 5203-5207. doi: 10.1016/j.bmcl.2015.09.066
101. Rasamiravaka, T., Vandeputte, O. M., Pottier, L., Huet, J., Rabemanantsoa, C., Kiendrebeogo, M., et al. (2015). Pseudomonas aeruginosa biofilm formation and persistence, along with the production of quorum sensing-dependent virulence factors, are disrupted by a triterpenoid coumarate ester isolated from Dalbergia trichocarpa, a tropical legume. PLoS ONE 10:e0132791. doi: 10.1371/journal.pone.0132791
102. Rasmussen, T. B., Bjarnsholt, T., Skindersoe, M. E., Hentzer, M., Kristoffersen, P., Kote, M., et al. (2005). Screening for quorum-sensing inhibitors (QSI) by use of a novel genetic system, the QSI selector. J. Bacteriol. 187, 1799-1814. doi: 10.1128/JB.187.5.1799-1814.2005
103. Roeder, T., Stanisak, M., Gelhaus, C., Bruchhaus, I., Grotzinger, J., and Leippe, M. (2010). Caenopores are antimicrobial peptides in the nematode Caenorhabditis elegans instrumental in nutrition and immunity. Dev. Comp. Immunol. 34, 203-209. doi: 10.1016/j.dci.2009.09.010
104. Rual, J. F., Ceron, J., Koreth, J., Hao, T., Nicot, A. S., Hirozane-Kishikawa, T., et al. (2004). Toward improving Caenorhabditis elegans phenome mapping with an ORFeome-based RNAi library. Genome Res. 14, 2162-2168. doi: 10.1101/gr.2505604
105. Rudrappa, T., and Bais, H. P. (2008). Curcumin, a known phenolic from Curcuma longa, attenuates the virulence of Pseudomonas aeruginosa PAO1 in whole plant and animal pathogenicity models. J. Agric. Food Chem. 56, 1955-1962. doi: 10.1021/jf072591j
106. Sarabhai, S., Sharma, P., and Capalash, N. (2013). Ellagic acid derivatives from Terminalia chebula Retz. downregulate the expression of quorum sensing genes to attenuate Pseudomonas aeruginosa PAO1 virulence. PLoS ONE 8:e53441. doi: 10.1371/journal.pone.0053441
107. Schulenburg, H., and Boehnisch, C. (2008). Diversification and adaptive sequence evolution of Caenorhabditis lysozymes (Nematoda: Rhabditidae). BMC Evol. Biol. 8:114. doi: 10.1186/1471-2148-8-114
108. Schulenburg, H., and Ewbank, J. J. (2004). Diversity and specificity in the interaction between Caenorhabditis elegans and the pathogen Serratia marcescens. BMC Evol. Biol. 4:49. doi: 10.1186/1471-2148-4-49
109. Selin, C., Stietz, M. S., Blanchard, J. E., Gehrke, S. S., Bernard, S., Hall, D. G., et al. (2015). A pipeline for screening small molecules with growth inhibitory activity against Burkholderia cenocepacia. PLoS ONE 10:e0128587. doi: 10.1371/journal.pone.0128587
110. Shapira, M., Hamlin, B. J., Rong, J., Chen, K., Ronen, M., and Tan, M. W. (2006). A conserved role for a GATA transcription factor in regulating epithelial innate immune responses. Proc. Natl. Acad. Sci. U.S.A. 103, 14086-14091. doi: 10.1073/pnas.0603424103
111. Sifri, C. D., Begun, J., Ausubel, F. M., and Calderwood, S. B. (2003). Caenorhabditis elegans as a model host for Staphylococcus aureus pathogenesis. Infect. Immun. 71, 2208-2217. doi: 10.1128/IAI.71.4.2208-2217.2003
112. Silva, A., Genoves, S., Martorell, P., Zanini, S. F., Rodrigo, D., and Martinez, A. (2015). Sublethal injury and virulence changes in Listeria monocytogenes and Listeria innocua treated with antimicrobials carvacrol and citral. Food Microbiol. 50, 5-11. doi: 10.1016/j.fm.2015.02.016
113. Sivaranjani, M., Gowrishankar, S., Kamaladevi, A., Pandian, S. K., Balamurugan, K., and Ravi, A. V. (2016). Morin inhibits biofilm production and reduces the virulence of Listeria monocytogenes-an in vitro and in vivo approach. Int. J. Food Microbiol. 237, 73-82. doi: 10.1016/j.ijfoodmicro.2016.08.021
114. Stokes, J. M., Selin, C., Cardona, S. T., and Brown, E. D. (2015). Chemical inhibition of bacterial ribosome biogenesis shows efficacy in a worm infection model. Antimicrob. Agents Chemother. 59, 2918-2920. doi: 10.1128/AAC.04690-14
115. Tan, M. W., Rahme, L. G., Sternberg, J. A., Tompkins, R. G., and Ausubel, F. M. (1999). Pseudomonas aeruginosa killing of Caenorhabditis elegans used to identify P. aeruginosa virulence factors. Proc. Natl. Acad. Sci. U.S.A. 96, 2408-2413. doi: 10.1073/pnas.96.5.2408
116. Tarr, D. E. (2012). Distribution and characteristics of ABFs, cecropins, nemapores, and lysozymes in nematodes. Dev. Comp. Immunol. 36, 502-520. doi: 10.1016/j.dci.2011.09.007
117. Thangamani, S., Younis, W., and Seleem, M. N. (2015). Repurposing celecoxib as a topical antimicrobial agent. Front. Microbiol. 6:750. doi: 10.3389/fmicb.2015.00750
118. Tomkiewicz, D., Casadei, G., Larkins-Ford, J., Moy, T. I., Garner, J., Bremner, J. B., et al. (2010). Berberine-INF55 (5-nitro-2-phenylindole) hybrid antimicrobials: effects of varying the relative orientation of the berberine and INF55 components. Antimicrob. Agents Chemother. 54, 3219-3224. doi: 10.1128/AAC.01715-09
119. Troemel, E. R., Chu, S. W., Reinke, V., Lee, S. S., Ausubel, F. M., and Kim, D. H. (2006). p38 MAPK regulates expression of immune response genes and contributes to longevity in C. elegans. PLoS Genet. 2:e183. doi: 10.1371/journal.pgen.0020183
120. Uccelletti, D., Zanni, E., Marcellini, L., Palleschi, C., Barra, D., and Mangoni, M. L. (2010). Anti-Pseudomonas activity of frog skin antimicrobial peptides in a Caenorhabditis elegans infection model: a plausible mode of action in vitro and in vivo. Antimicrob. Agents Chemother. 54, 3853-3860. doi: 10.1128/AAC.00154-10
121. Ueda, A., Attila, C., Whiteley, M., and Wood, T. K. (2009). Uracil influences quorum sensing and biofilm formation in Pseudomonas aeruginosa and fluorouracil is an antagonist. Microb. Biotechnol. 2, 62-74. doi: 10.1111/j.1751-7915.2008.00060.x
122. Van Herreweghe, J. M., and Michiels, C. W. (2012). Invertebrate lysozymes: diversity and distribution, molecular mechanism and in vivo function. J. Biosci. (Bangalore) 37, 327-348. doi: 10.1007/s12038-012-9201-y
123. Wahlby, C., Kamentsky, L., Liu, Z. H., Riklin-Raviv, T., Conery, A. L., O'rourke, E. J., et al. (2012). An image analysis toolbox for high-throughput C. elegans assays. Nat. Methods 9, 714-716. doi: 10.1038/nmeth.1984
124. Wang, J., Zhou, X., Li, W., Deng, X., Deng, Y., and Niu, X. (2016). Curcumin protects mice from Staphylococcus aureus pneumonia by interfering with the self-assembly process of alpha-hemolysin. Sci. Rep. 6:28254. doi: 10.1038/srep28254
125. Williams, P., Winzer, K., Chan, W. C., and Camara, M. (2007). Look who's talking: communication and quorum sensing in the bacterial world. Philos. Trans. R. Soc. Lond. B Biol. Sci. 362, 1119-1134. doi: 10.1098/rstb.2007.2039
126. Yamamoto, K., Kitayama, T., Ishida, N., Watanabe, T., Tanabe, H., Takatani, M., et al. (2000). Identification and characterization of a potent antibacterial agent. NH125 against drug-resistant bacteria. Biosci. Biotechnol., Biochem. 64, 919-923. doi: 10.1271/bbb.64.919
127. Yang, J., Chen, Z., Ching, P., Shi, Q., and Li, X. (2013). An integrated microfluidic platform for evaluating in vivo antimicrobial activity of natural compounds using a whole-animal infection model. Lab. Chip 13, 3373-3382. doi: 10.1039/c3lc50264c
128. Yang, J., Huang, X., Tian, B., Wang, M., Niu, Q., and Zhang, K. (2005). Isolation and characterization of a serine protease from the nematophagous fungus, Lecanicillium psalliotae, displaying nematicidal activity. Biotechnol. Lett. 27, 1123-1128. doi: 10.1007/s10529-005-8461-0
129. Yin, H., Deng, Y., Wang, H., Liu, W., Zhuang, X., and Chu, W. (2015). Tea polyphenols as an antivirulence compound disrupt quorum-sensing regulated pathogenicity of Pseudomonas aeruginosa. Sci. Rep. 5:16158. doi: 10.1038/srep16158
130. Yun, B., Oh, S., Song, M., Hong, Y. S., Park, S., Park, D. J., et al. (2015). Inhibitory effect of epigallocatechin gallate on the virulence of Clostridium difficile PCR Ribotype 027. J. Food Sci. 80, M2925-M2931. doi: 10.1111/1750-3841.13145
131. Zhou, Y. M., Shao, L., Li, J. A., Han, L. Z., Cai, W. J., Zhu, C. B., et al. (2011). An efficient and novel screening model for assessing the bioactivity of extracts against multidrug-resistant Pseudomonas aeruginosa using Caenorhabditis elegans. Biosci. Biotechnol. Biochem. 75, 1746-1751. doi: 10.1271/bbb.110290
132. Zhu, J., Cai, X., Harris, T. L., Gooyit, M., Wood, M., Lardy, M., et al. (2015). Disarming Pseudomonas aeruginosa virulence factor LasB by leveraging a Caenorhabditis elegans infection model. Chem. Biol. 22, 483-491. doi: 10.1016/j.chembiol.2015.03.012
133. Zugasti, O., and Ewbank, J. J. (2009). Neuroimmune regulation of antimicrobial peptide expression by a noncanonical TGF-beta signaling pathway in Caenorhabditis elegans epidermis. Nat. Immunol. 10, 249-256. doi: 10.1038/ni.1700