Skip to main content
SpringerLink
Log in

Anti-MRSA agent discovery using Caenorhabditis elegans-based high-throughput screening

  • Minireview
  • Published:
Journal of Microbiology Aims and scope Submit manuscript

Abstract

Staphylococcus aureus is a leading cause of hospital- and community-acquired infections. Despite current advances in antimicrobial chemotherapy, the infections caused by S. aureus remain challenging due to their ability to readily develop resistance. Indeed, antibiotic resistance, exemplified by methicillin-resistant S. aureus (MRSA) is a top threat to global health security. Furthermore, the current rate of antibiotic discovery is much slower than the rate of antibiotic-resistance development. It seems evident that the conventional in vitro bacterial growth-based screening strategies can no longer effectively supply new antibiotics at the rate needed to combat bacterial antibiotic-resistance. To overcome this antibiotic resistance crisis, screening assays based on host–pathogen interactions have been developed. In particular, the free-living nematode Caenorhabditis elegans has been used for drug screening against MRSA. In this review, we will discuss the general principles of the C. elegans-based screening platform and will highlight its unique strengths by comparing it with conventional antibiotic screening platforms. We will outline major hits from high-throughput screens of more than 100,000 small molecules using the C. elegans–MRSA infection assay and will review the mode-of-action of the identified hit compounds. Lastly, we will discuss the potential of a C. elegans-based screening strategy as a paradigm shift screening platform.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Aboraia, A.S., Abdel-Rahman, H.M., Mahfouz, N.M., and El-Gendy, M.A. 2006. Novel 5-(2-hydroxyphenyl)-3-substituted-2, 3-dihydro-1, 3, 4-oxadiazole-2-thione derivatives: promising anticancer agents. Biorg. Med. Chem. 14, 1236–1246.

    CAS  Google Scholar 

  • Abouelhassan, Y., Basak, A., Yousaf, H., and Huigens, R.W. 3rd 2017. Identification of N-arylated NH125 analogues as rapid eradicating agents against MRSA persister cells and potent biofilm killers of Gram-positive pathogens. ChemBioChem 18, 352–357.

    CAS  PubMed  Google Scholar 

  • Al-Soud, Y.A., Al-Masoudi, N.A., and Ferwanah, A.E.R.S. 2003. Synthesis and properties of new substituted 1, 2, 4-triazoles: potential antitumor agents. Bioorg. Med. Chem. 11, 1701–1708.

    CAS  PubMed  Google Scholar 

  • Altucci, L., Leibowitz, M.D., Ogilvie, K.M., de Lera, A.R., and Gronemeyer, H. 2007. RAR and RXR modulation in cancer and metabolic disease. Nat. Rev. Drug Discov. 6, 793–810.

    CAS  PubMed  Google Scholar 

  • Álvarez, R., Vaz, B., Gronemeyer, H., and de Lera, Á.R. 2014. Functions, therapeutic applications, and synthesis of retinoids and carotenoids. Chem. Rev. 114, 1–125.

    PubMed  Google Scholar 

  • Anastassopoulou, C.G., Fuchs, B.B., and Mylonakis, E. 2011. Caenorhabditis elegans-based model systems for antifungal drug discovery. Curr. Pharm. Des. 17, 1225–1233.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Arora, S., Yang, J.M., Kinzy, T.G., Utsumi, R., Okamoto, T., Kitayama, T., Ortiz, P.A., and Hait, W.N. 2003. Identification and characterization of an inhibitor of eukaryotic elongation factor 2 kinase against human cancer cell lines. Cancer Res. 63, 6894–6899.

    CAS  PubMed  Google Scholar 

  • Balaban, N.Q., Helaine, S., Lewis, K., Ackermann, M., Aldridge, B., Andersson, D.I., Brynildsen, M.P., Bumann, D., Camilli, A., Collins, J.J., et al. 2019. Definitions and guidelines for research on antibiotic persistence. Nat. Rev. Microbiol. 17, 441–448.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Basak, A., Abouelhassan, Y., Zuo, R., Yousaf, H., Ding, Y., and Huigens, R.W. 2017. Antimicrobial peptide-inspired NH125 analogues: bacterial and fungal biofilm-eradicating agents and rapid killers of MRSA persisters. Org. Biomol. Chem. 15, 5503–5512.

    CAS  PubMed  Google Scholar 

  • Berger, J.P., Petro, A.E., Macnaul, K.L., Kelly, L.J., Zhang, B.B., Richards, K., Elbrecht, A., Johnson, B.A., Zhou, G., Doebber, T.W., et al. 2003. Distinct properties and advantages of a novel peroxisome proliferator-activated protein γ selective modulator. Mol. Endocrinol. 17, 662–676.

    CAS  PubMed  Google Scholar 

  • Bigger, J.W. 1944. Treatment of staphylococcal infections with penicillin by intermittent sterilisation. Lancet 244, 497–500.

    Google Scholar 

  • Carpenter, A.E., Jones, T.R., Lamprecht, M.R., Clarke, C., Kang, I.H., Friman, O., Guertin, D.A., Chang, J.H., Lindquist, R.A., Moffat, J., et al. 2006. CellProfiler: image analysis software for identifying and quantifying cell phenotypes. Genome Biol. 7, R100.

    PubMed  PubMed Central  Google Scholar 

  • Casadevall, A. and Pirofski, L. 2001. Host-pathogen interactions: the attributes of virulence. J. Infect. Dis. 184, 337–344.

    CAS  PubMed  Google Scholar 

  • Chang, S., Sievert, D.M., Hageman, J.C., Boulton, M.L., Tenover, F.C., Downes, F.P., Shah, S., Rudrik, J.T., Pupp, G.R., Brown, W.J., et al. 2003. Infection with vancomycin-resistant Staphylococcus aureus containing the vanA resistance gene. N. Engl. J. Med. 348, 1342–1347.

    PubMed  Google Scholar 

  • Chen, Z., Gopalakrishnan, S.M., Bui, M.H., Soni, N.B., Warrior, U., Johnson, E.F., Donnelly, J.B., and Glaser, K.B. 2011. 1-Benzyl-3-cetyl-2-methylimidazolium iodide (NH125) induces phosphorylation of eukaryotic elongation factor-2 (eEF2) a cautionary note on the anticancer mechanism of an eEF2 kinase inhibitor. J. Biol. Chem. 286, 43951–43958.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chiang, C.Y., Uzoma, I., Moore, R.T., Gilbert, M., Duplantier, A.J., and Panchal, R.G. 2018. Mitigating the impact of antibacterial drug resistance through host-directed therapies: current progress, outlook, and challenges. mBio 9, e01932–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Clarke, S.R., Harris, L.G., Richards, R.G., and Foster, S.J. 2002. Analysis of Ebh, a 1.1-megadalton cell wall-associated fibronectinbinding protein of Staphylococcus aureus. Infect. Immun. 70, 6680–6687.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Clatworthy, A.E., Romano, K.P., and Hung, D.T. 2018. Whole-organism phenotypic screening for anti-infectives promoting host health. Nat. Chem. Biol. 14, 331–341.

    CAS  PubMed  Google Scholar 

  • Cooper, V.S., Carlson, W.A., and LiPuma, J.J. 2009. Susceptibility of Caenorhabditis elegans to Burkholderia infection depends on prior diet and secreted bacterial attractants. PLoS One 4, e7961.

    PubMed  PubMed Central  Google Scholar 

  • Cunningham, T.J. and Duester, G. 2015. Mechanisms of retinoic acid signalling and its roles in organ and limb development. Nat. Rev. Mol. Cell Biol. 16, 110–123.

    CAS  PubMed  PubMed Central  Google Scholar 

  • de la Torre, B.G. and Albericio, F. 2020. The pharmaceutical industry in 2019. An analysis of FDA drug approvals from the perspective of molecules. Molecules 25, E745.

    PubMed  Google Scholar 

  • Domagk, G. 1935. Ein beitrag zur chemotherapie der bakteriellen infektionen. Dtsch. Med. Wochenschr. 61, 250–253.

    CAS  Google Scholar 

  • El-Emam, A.A., Al-Deeb, O.A., Al-Omar, M., and Lehmann, J. 2004. Synthesis, antimicrobial, and anti-HIV-1 activity of certain 5-(1-adamantyl)-2-substituted thio-1, 3, 4-oxadiazoles and 5-(1-adamantyl)-3-substituted aminomethyl-1, 3, 4-oxadiazoline-2-thiones. Bioorg. Med. Chem. 12, 5107–5113.

    CAS  PubMed  Google Scholar 

  • Farha, M.A., Verschoor, C.P., Bowdish, D., and Brown, E.D. 2013. Collapsing the proton motive force to identify synergistic combinations against Staphylococcus aureus. Chem. Biol. 20, 1168–1178.

    CAS  PubMed  Google Scholar 

  • Feng, X., Zhu, W., Schurig-Briccio, L.A., Lindert, S., Shoen, C., Hitchings, R., Li, J., Wang, Y., Baig, N., Zhou, T., et al. 2015. Antiinfectives targeting enzymes and the proton motive force. Proc. Natl. Acad. Sci. USA 112, E7073–E7082.

    CAS  PubMed  Google Scholar 

  • Foster, T.J. 2017. Antibiotic resistance in Staphylococcus aureus. Current status and future prospects. FEMS Microbiol. Rev. 41, 430–449.

    CAS  PubMed  Google Scholar 

  • Gan, Y.H., Chua, K.L., Chua, H.H., Liu, B.P., Hii, C.S., Chong, H.L., and Tan, P. 2002. Characterization of Burkholderia pseudomallei infection and identification of novel virulence factors using a Caenorhabditis elegans host system. Mol. Mirobiol. 44, 1185–1197.

    CAS  Google Scholar 

  • Garsin, D.A., Sifri, C.D., Mylonakis, E., Qin, X., Singh, K.V., Murray, B.E., Calderwood, S.B., and Ausubel, F.M. 2001. A simple model host for identifying Gram-positive virulence factors. Proc. Natl. Acad. Sci. USA 98, 10892–10897.

    CAS  PubMed  Google Scholar 

  • Gollan, B., Grabe, G., Michaux, C., and Helaine, S. 2019. Bacterial persisters and infection: Past, present, and progressing. Annu. Rev. Microbiol. 73, 359–385.

    CAS  PubMed  Google Scholar 

  • Gordon, R.J. and Lowy, F.D. 2008. Pathogenesis of methicillin-resistant Staphylococcus aureus infection. Clin. Infect. Dis. 46, S350–359.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gwisai, T., Hollingsworth, N.R., Cowles, S., Tharmalingam, N., Mylonakis, E., Fuchs, B.B., and Shukla, A. 2017. Repurposing niclosamide as a versatile antimicrobial surface coating against deviceassociated, hospital-acquired bacterial infections. Biomed. Mater. 12, 045010.

    PubMed  PubMed Central  Google Scholar 

  • Han, T., Goralski, M., Capota, E., Padrick, S.B., Kim, J., Xie, Y., and Nijhawan, D. 2016. The antitumor toxin CD437 is a direct inhibitor of DNA polymerase a. Nat. Chem. Biol. 12, 511–515.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Harbut, M.B., Vilchèze, C., Luo, X., Hensler, M.E., Guo, H., Yang, B., Chatterjee, A.K., Nizet, V., Jacobs, W.R. Jr., Schultz, P.G., et al. 2015. Auranofin exerts broad-spectrum bactericidal activities by targeting thiol-redox homeostasis. Proc. Natl. Acad. Sci. USA 112, 4453–4458.

    CAS  PubMed  Google Scholar 

  • Hlasta, D.J., Demers, J.P., Foleno, B.D., Fraga-Spano, S.A., Guan, J., Hilliard, J.J., Macielag, M.J., Ohemeng, K.A., Sheppard, C.M., Sui, Z., et al. 1998. Novel inhibitors of bacterial two-component systems with Gram positive antibacterial activity: pharmacophore identification based on the screening hit closantel. Bioorg. Med. Chem. Lett. 8, 1923–1928.

    CAS  PubMed  Google Scholar 

  • Hobby, G.L., Meyer, K., and Chaffee, E. 1942. Observations on the mechanism of action of penicillin. Proc. Soc. Exp. Biol. Med. 50, 281–285.

    CAS  Google Scholar 

  • Hummell, N.A. and Kirienko, N.V. 2020. Repurposing bioactive compounds for treating multidrug-resistant pathogens. J. Med. Microbiol. DOI: https://doi.org/10.1099/jmm.0.001172.

    Google Scholar 

  • Hurdle, J.G., O'Neill, A.J., Chopra, I., and Lee, R.E. 2011. Targeting bacterial membrane function: an underexploited mechanism for treating persistent infections. Nat. Rev. Microbiol. 9, 62–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Irazoqui, J.E., Troemel, E.R., Feinbaum, R.L., Luhachack, L.G., Cezairliyan, B.O., and Ausubel, F.M. 2010a. Distinct pathogenesis and host responses during infection of C. elegans by P. aeruginosa and S. aureus. PLoS Pathog., 6, e1000982.

    PubMed  PubMed Central  Google Scholar 

  • Irazoqui, J.E., Urbach, J.M., and Ausubel, F.M. 2010b. Evolution of host innate defence: insights from Caenorhabditis elegans and primitive invertebrates. Nat. Rev. Immunol., 10, 47–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Irby, C.E., Yentzer, B.A., and Feldman, S.R. 2008. A review of adapalene in the treatment of acne vulgaris. J. Adolesc. Health 43, 421–424.

    PubMed  Google Scholar 

  • Jayamani, E., Rajamuthiah, R., Larkins-Ford, J., Fuchs, B.B., Conery, A.L., Vilcinskas, A., Ausubel, F.M., and Mylonakis, E. 2015. Insectderived cecropins display activity against Acinetobacter baumannii in a whole-animal high-throughput Caenorhabditis elegans model. Antimicrob. Agents Chemother. 59, 1728–1737.

    PubMed  PubMed Central  Google Scholar 

  • Jayamani, E., Tharmalingam, N., Rajamuthiah, R., Coleman, J.J., Kim, W., Okoli, I., Hernandez, A.M., Lee, K., Nau, G.J., Ausubel, F.M., et al. 2017. Characterization of a Francisella tularensis-Caenorhabditis elegans pathosystem for the evaluation of therapeutic compounds. Antimicrob. Agents Chemother. 61, e00310–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Johnston, T., Hendricks, G.L., Shen, S., Chen, R.F., Kwon, B., Kelso, M.J., Kim, W., Burgwyn Fuchs, B., and Mylonakis, E. 2016. Rafkinase inhibitor GW5074 shows antibacterial activity against methicillin-resistant Staphylococcus aureus and potentiates the activity of gentamicin. Future Med. Chem. 8, 1941–1952.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Johnston, T., Van Tyne, D., Chen, R.F., Fawzi, N.L., Kwon, B., Kelso, M.J., Gilmore, M.S., and Mylonakis, E. 2018. Propyl-5-hydroxy-3-methyl-1-phenyl-1 H-pyrazole-4-carbodithioate (HMPC): a new bacteriostatic agent against methicillin-resistant Staphylococcus aureus. Sci. Rep. 8, 1–12.

    Google Scholar 

  • Keiser, J. and Utzinger, J. 2007. Food-borne trematodiasis: current chemotherapy and advances with artemisinins and synthetic trioxolanes. Trends Parasitol. 23, 555–562.

    CAS  PubMed  Google Scholar 

  • 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.

    PubMed  PubMed Central  Google Scholar 

  • Kim, W., Fricke, N., Conery, A.L., Fuchs, B.B., Rajamuthiah, R., Jayamani, E., Vlahovska, P.M., Ausubel, F.M., and Mylonakis, E. 2016. NH125 kills methicillin-resistant Staphylococcus aureus persisters by lipid bilayer disruption. Future Med. Chem. 8, 257–269.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kim, W., Hendricks, G.L., Lee, K., and Mylonakis, E. 2017. An update on the use of C. elegans for preclinical drug discovery: screening and identifying anti-infective drugs. Expert Opin. Drug Discov. 12, 625–633.

    CAS  PubMed  Google Scholar 

  • Kim, W., Steele, A.D., Zhu, W.P., Csatary, E.E., Fricke, N., Dekarske, M.M., Jayamani, E., Pan, W., Kwon, B., Sinitsa, I.F., et al. 2018a. Discovery and optimization of nTZDpa as an antibiotic effective against bacterial persisters. ACS Infect. Dis. 4, 1540–1545.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kim, W., Zhu, W., Hendricks, G.L., Van Tyne, D., Steele, A.D., Keohane, C.E., Fricke, N., Conery, A.L., Shen, S., Pan, W., et al. 2018b. A new class of synthetic retinoid antibiotics effective against bacterial persisters. Nature 556, 103–107.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kim, W., Zou, G., Hari, T.P.A., Wilt, I.K., Zhu, W., Galle, N., Faizi, H.A., Hendricks, G.L., Tori, K., Pan, W., et al. 2019. A selective membrane-targeting repurposed antibiotic with activity against persistent methicillin-resistant Staphylococcus aureus. Proc. Natl. Acad. Sci. USA 116, 16529–16534.

    CAS  PubMed  Google Scholar 

  • Kirienko, N.V., Kirienko, D.R., Larkins-Ford, J., Wählby, 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Klevens, R.M., Morrison, M.A., Nadle, J., Petit, S., Gershman, K., Ray, S., Harrison, L.H., Lynfield, R., Dumyati, G., Townes, J.M., et al. 2007. Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA 298, 1763–1771.

    CAS  PubMed  Google Scholar 

  • Kourtis, A.P., Hatfield, K., Baggs, J., Mu, Y., See, I., Epson, E., Nadle, J., Kainer, M.A., Dumyati, G., Petit, S., et al. 2019. Vital signs: Epidemiology and recent trends in methicillin-resistant and in methicillin-susceptible Staphylococcus aureus bloodstream infections - United States. MMWR Morb. Mortal. Wkly. Rep. 68, 214–219.

    PubMed  PubMed Central  Google Scholar 

  • Lavoie, H. and Therrien, M. 2015. Regulation of RAF protein kinases in ERK signalling. Nat. Rev. Mol. Cell Biol. 16, 281–298.

    CAS  PubMed  Google Scholar 

  • Lewis, K. 2010. Persister cells. Annu. Rev. Microbiol. 64, 357–372.

    CAS  PubMed  Google Scholar 

  • Lewis, K. 2013. Platforms for antibiotic discovery. Nat. Rev. Drug Discov. 12, 371–387.

    CAS  PubMed  Google Scholar 

  • Ling, L.L., Schneider, T., Peoples, A.J., Spoering, A.L., Engels, I., Conlon, B.P., Mueller, A., Schäberle, T.F., Hughes, D.E., Epstein, S., et al. 2015. A new antibiotic kills pathogens without detectable resistance. Nature 517, 455–459.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liu, Q., Zheng, Z., Kim, W., Burgwyn Fuchs, B., and Mylonakis, E. 2018. Influence of subinhibitory concentrations of NH125 on biofilm formation & virulence factors of Staphylococcus aureus. Future Med. Chem. 10, 1319–1331.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lowy, F.D. 2003. Antimicrobial resistance: the example of Staphylococcus aureus. J. Clin. Invest. 111, 1265–1273.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Luong, T.T., Dunman, P.M., Murphy, E., Projan, S.J., and Lee, C.Y. 2006. Transcription profiling of the mgrA regulon in Staphylococcus aureus. J. Bacteriol. 188, 1899–1910.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mahajan-Miklos, S., Tan, M.W., Rahme, L.G., and Ausubel, F.M. 1999. Molecular mechanisms of bacterial virulence elucidated using a Pseudomonas aeruginosa-Caenorhabditis elegans pathogenesis model. Cell 96, 47–56.

    CAS  PubMed  Google Scholar 

  • Mangili, A., Bica, I., Snydman, D.R., and Hamer, D.H. 2005. Daptomycin- resistant, methicillin-resistant Staphylococcus aureus bacteremia. Clin. Infect. Dis. 40, 1058–1060.

    CAS  PubMed  Google Scholar 

  • Merino, N., Toledo-Arana, A., Vergara-Irigaray, M., Valle, J., Solano, C., Calvo, E., Lopez, J.A., Foster, T.J., Penadés, J.R., and Lasa, I. 2009. Protein A-mediated multicellular behavior in Staphylococcus aureus. J. Bacteriol. 191, 832–843.

    CAS  PubMed  Google Scholar 

  • Meylan, S., Andrews, I.W., and Collins, J.J. 2018. Targeting antibiotic tolerance, pathogen by pathogen. Cell 172, 1228–1238.

    CAS  PubMed  Google Scholar 

  • Mikkaichi, T., Yeaman, M.R., Hoffmann, A., and MRSA Systems Immunobiology Group. 2019. Identifying determinants of persistent MRSA bacteremia using mathematical modeling. PLoS Comput. Biol. 15, e1007087.

    PubMed  PubMed Central  Google Scholar 

  • Mingeot-Leclercq, M.P. and Décout, J.L. 2016. Bacterial lipid membranes as promising targets to fight antimicrobial resistance, molecular foundations and illustration through the renewal of aminoglycoside antibiotics and emergence of amphiphilic aminoglycosides. Med. Chem. Commun. 7, 586–611.

    CAS  Google Scholar 

  • 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. USA 103, 10414–10419.

    CAS  PubMed  Google Scholar 

  • Moy, T.I., Conery, A.L., Larkins-Ford, J., Wu, G., Mazitschek, R., Casadei, G., Lewis, K., Carpenter, A.E., and Ausubel, F.M. 2009. High-throughput screen for novel antimicrobials using a whole animal infection model. ACS Chem. Biol. 4, 527–533.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Munguia, J. and Nizet, V. 2017. Pharmacological targeting of the host-pathogen interaction: Alternatives to classical antibiotics to combat drug-resistant superbugs. Trends Pharmacol. Sci. 38, 473–488.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mylonakis, E. and Aballay, A. 2005. Worms and flies as genetically tractable animal models to study host-pathogen interactions. Infect. Immun. 73, 3833–3841.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Narayana, B., Ashalatha, B.V., Vijaya Raj, K.K., Fernandes, J., and Sarojini, B. 2005. Synthesis of some new biologically active 1,3,4-oxadiazolyl nitroindoles and a modified Fischer indole synthesis of ethyl nitro indole-2-carboxylates. Bioorg. Med. Chem. 13, 4638–4644.

    CAS  PubMed  Google Scholar 

  • Nicolaou, K.C. and Rigol, S. 2018. A brief history of antibiotics and select advances in their synthesis. J. Antibiot. 71, 153–184.

    CAS  PubMed  Google Scholar 

  • Nieto-Rementeria, N., Pérez-Yarza, G., Boyano, M., Apraiz, A., Izu, R., Díaz-Pérez, J., and Asumendi, A. 2009. Bexarotene activates the p53/p73 pathway in human cutaneous T-cell lymphoma. Br. J. Dermatol. 160, 519–526.

    CAS  PubMed  Google Scholar 

  • O'Keeffe, K.M., Wilk, M.M., Leech, J.M., Murphy, A.G., Laabei, M., Monk, I.R., Massey, R.C., Lindsay, J.A., Foster, T.J., Geoghegan, J.A., et al. 2015. Manipulation of autophagy in phagocytes facilitates Staphylococcus aureus bloodstream infection. Infect. Immun. 83, 3445–3457.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Otto, M. 2012. MRSA virulence and spread. Cell. Microbiol. 14, 1513–1521.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Peschel, A., Jack, R.W., Otto, M., Collins, L.V., Staubitz, P., Nicholson, G., Kalbacher, H., Nieuwenhuizen, W.F., Jung, G., Tarkowski, A., et al. 2001. Staphylococcus aureus resistance to human defensins and evasion of neutrophil killing via the novel virulence factor Mprf is based on modification of membrane lipids with L-lysine. J. Exp. Med. 193, 1067–1076.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Peterson, N.D. and Pukkila-Worley, R. 2018. Caenorhabditis elegans in high-throughput screens for anti-infective compounds. Curr. Opin. Immunol. 54, 59–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pukkila-Worley, R. and Ausubel, F.M. 2012. Immune defense mechanisms in the Caenorhabditis elegans intestinal epithelium. Curr. Opin. Immunol. 24, 3–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rajamuthiah, R., Fuchs, B.B., Conery, A.L., Kim, W., Jayamani, E., Kwon, B., Ausubel, F.M., and Mylonakis, E. 2015a. Repurposing salicylanilide anthelmintic drugs to combat drug resistant Staphylococcus aureus. PLoS One 10, e0124595.

    PubMed  PubMed Central  Google Scholar 

  • Rajamuthiah, R., Fuchs, B.B., Jayamani, E., Kim, Y., Larkins-Ford, J., Conery, A., Ausubel, F.M., and Mylonakis, E. 2014. Whole animal automated platform for drug discovery against multidrug resistant Staphylococcus aureus. PLoS One 9, e89189.

    PubMed  PubMed Central  Google Scholar 

  • Rajamuthiah, R., Jayamani, E., Majed, H., Conery, A.L., Kim, W., Kwon, B., Fuchs, B.B., Kelso, M.J., Ausubel, F.M., and Mylonakis, E. 2015b. Antibacterial properties of 3-(phenylsulfonyl)-2-pyrazinecarbonitrile. Bioorg. Med. Chem. Lett. 25, 5203–5207.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rammelkamp, C.H. and Maxon, T. 1942. Resistance of Staphylococcus aureus to the action of penicillin. Procs. Soc. Exp. Biol. Med. 51, 386–389.

    CAS  Google Scholar 

  • Rautio, J., Meanwell, N.A., Di, L., and Hageman, M.J. 2018. The expanding role of prodrugs in contemporary drug design and development. Nat. Rev. Drug Discov. 17, 559–587.

    CAS  PubMed  Google Scholar 

  • Richter, S.G., Elli, D., Kim, H.K., Hendrickx, A.P., Sorg, J.A., Schneewind, O., and Missiakas, D. 2013. Small molecule inhibitor of lipoteichoic acid synthesis is an antibiotic for Gram-positive bacteria. Proc. Natl. Acad. Sci. USA 110, 3531–3536.

    CAS  PubMed  Google Scholar 

  • Roth, B.L., Poot, M., Yue, S.T., and Millard, P.J. 1997. Bacterial viability and antibiotic susceptibility testing with SYTOX green nucleic acid stain. Appl. Environ. Microbiol. 63, 2421–2431.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Scott, E., Holden-Dye, L., O'Connor, V., and Wand, M.E. 2019. Intra strain variation of the effects of Gram-negative ESKAPE pathogens on intestinal colonization, host viability, and host response in the model organism Caenorhabditis elegans. Front. Microbiol. 10, 3113.

    PubMed  Google Scholar 

  • Shimono, K., Tung, W.E., Macolino, C., Chi, A.H., Didizian, J.H., Mundy, C., Chandraratna, R.A., Mishina, Y., Enomoto-Iwamoto, M., Pacifici, M., et al. 2011. Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-γ agonists. Nat. Med. 17, 454–460.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sifri, C.D., Begun, J., and Ausubel, F.M. 2005. The worm has turnedmicrobial virulence modeled in Caenorhabditis elegans. Trends Microbiol. 13, 119–127.

    CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tan, M.W., Mahajan-Miklos, S., and Ausubel, F.M. 1999. Killing of Caenorhabditis elegans by Pseudomonas aeruginosa used to model mammalian bacterial pathogenesis. Proc. Natl. Acad. Sci. USA 96, 715–720.

    CAS  PubMed  Google Scholar 

  • Tang, X.H. and Gudas, L.J. 2011. Retinoids, retinoic acid receptors, and cancer. Annu. Rev. Pathol. 6, 345–364.

    CAS  PubMed  Google Scholar 

  • Tang, X.H., Osei-Sarfo, K., Urvalek, A.M., Zhang, T., Scognamiglio, T., and Gudas, L.J. 2014. Combination of bexarotene and the retinoid CD1530 reduces murine oral-cavity carcinogenesis induced by the carcinogen 4-nitroquinoline 1-oxide. Proc. Natl. Acad. Sci. USA 111, 8907–8912.

    CAS  PubMed  Google Scholar 

  • Thacher, S.M., Vasudevan, J., and Chandraratna, R.A. 2000. Therapeutic applications for ligands of retinoid receptors. Curr. Pharm. Des. 6, 25–58.

    CAS  PubMed  Google Scholar 

  • Tharmalingam, N., Jayamani, E., Rajamuthiah, R., Castillo, D., Fuchs, B.B., Kelso, M.J., and Mylonakis, E. 2017. Activity of a novel protonophore against methicillin-resistant Staphylococcus aureus. Future Med. Chem. 9, 1401–1411.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tharmalingam, N., Khader, R., Fuchs, B.B., and Mylonakis, E. 2019. The anti-virulence efficacy of 4-(1,3-dimethyl-2,3-dihydro-1Hbenzimidazol-2-yl)phenol against methicillin-resistant Staphylococcus aureus. Front. Microbiol. 10, 1557.

    PubMed  PubMed Central  Google Scholar 

  • Tharmalingam, N., Port, J., Castillo, D., and Mylonakis, E. 2018a. Repurposing the anthelmintic drug niclosamide to combat Helicobacter pylori. Sci. Rep. 8, 3701.

    PubMed  PubMed Central  Google Scholar 

  • Tharmalingam, N., Rajmuthiah, R., Kim, W., Fuchs, B.B., Jeyamani, E., Kelso, M.J., and Mylonakis, E. 2018b. Antibacterial properties of four novel hit compounds from a methicillin-resistant Staphylococcus aureus-Caenorhabditis elegans high-throughput screen. Microb. Drug Resist. 24, 666–674.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tong, S.Y., Davis, J.S., Eichenberger, E., Holland, T.L., and Fowler, V.G. Jr. 2015. Staphylococcus aureus infections: Epidemiology, pathophysiology, clinical manifestations, and management. Clin. Microbiol. Rev. 28, 603–661.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Troeman, D.P.R., Van Hout, D., and Kluytmans, J.A.J.W. 2019. Antimicrobial approaches in the prevention of Staphylococcus aureus infections: a review. J. Antimicrob. Chemother. 74, 281–294.

    CAS  PubMed  Google Scholar 

  • Tschierske, M., Mori, C., Rohrer, S., Ehlert, K., Shaw, K.J., and Berger-Bächi, B. 1999. Identification of three additional femAB-like open reading frames in Staphylococcus aureus. FEMS Microbiol. Lett. 171, 97–102.

    CAS  PubMed  Google Scholar 

  • Tsiodras, S., Gold, H.S., Sakoulas, G., Eliopoulos, G.M., Wennersten, C., Venkataraman, L., Moellering, R.C., and Ferraro, M.J. 2001. Linezolid resistance in a clinical isolate of Staphylococcus aureus. Lancet 358, 207–208.

    CAS  PubMed  Google Scholar 

  • Valentino, M.D., Foulston, L., Sadaka, A., Kos, V.N., Villet, R.A., Santa Maria, J. Jr., Lazinski, D.W., Camilli, A., Walker, S., Hooper, D.C., et al. 2014. Genes contributing to Staphylococcus aureus fitness in abscess- and infection-related ecologies. mBio 5, e01729–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Valli, C., Paroni, G., Di Francesco, A.M., Riccardi, R., Tavecchio, M., Erba, E., Boldetti, A., Gianni, M., Fratelli, M., Pisano, C., et al. 2008. Atypical retinoids ST1926 and CD437 are S-phase-specific agents causing DNA double-strand breaks: significance for the cytotoxic and antiproliferative activity. Mol. Cancer Ther. 7, 2941–2954.

    CAS  PubMed  Google Scholar 

  • Yamamoto, K., Kitayama, T., Ishida, N., Watanabe, T., Tanabe, H., Takatani, M., Okamoto, T., and Utsumi, R. 2000. Identification and characterization of a potent antibacterial agent, NH125 against drug-resistant bacteria. Biosci. Biotechnol. Biochem. 64, 919–923.

    CAS  PubMed  Google Scholar 

  • Yamamoto, K., Kitayama, T., Minagawa, S., Watanabe, T., Sawada, S., Okamoto, T., and Utsumi, R. 2001. Antibacterial agents that inhibit histidine protein kinase YycG of Bacillus subtilis. Biosci. Biotechnol. Biochem. 65, 2306–2310.

    CAS  PubMed  Google Scholar 

  • Zhao, X. and Spanjaard, R.A. 2003. The apoptotic action of the retinoid CD437/AHPN: diverse effects, common basis. J. Biomed. Sci. 10, 44–49.

    CAS  PubMed  Google Scholar 

  • Zheng, Z., Liu, Q., Kim, W., Tharmalingam, N., Fuchs, B.B., and Mylonakis, E. 2018. Antimicrobial activity of 1,3,4-oxadiazole derivatives against planktonic cells and biofilm of Staphylococcus aureus. Future Med. Chem. 10, 283–296.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea government (MSIT) (No. 2020R1C1C1008842, 2018R1A5A2025286 and 2017M3A9E4077234) and the Ewha Womans University Research Grant of 2019 to W.K. and National Institutes of Health Grant P01AI083214 to E.M.

Author information

Authors and Affiliations

  1. College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea

    Soo Min Kim & Wooseong Kim

  2. Division of Infectious Diseases, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island, 02903, USA

    Iliana Escorbar, Kiho Lee, Beth Burgwyn Fuchs & Eleftherios Mylonakis

Authors
  1. Soo Min Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Iliana Escorbar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kiho Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Beth Burgwyn Fuchs
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Eleftherios Mylonakis
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wooseong Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wooseong Kim.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, S.M., Escorbar, I., Lee, K. et al. Anti-MRSA agent discovery using Caenorhabditis elegans-based high-throughput screening. J Microbiol. 58, 431–444 (2020). https://doi.org/10.1007/s12275-020-0163-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12275-020-0163-8

Keywords

Search

Navigation