1887

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Volume 69, Issue 6

Repurposing bioactive compounds for treating multidrug-resistant pathogens Free

Abstract

Antimicrobial development is being outpaced by the rising rate of antimicrobial resistance in the developing and industrialized world. Drug repurposing, where novel antibacterial functions can be found for known molecular entities, reduces drug development costs, reduces regulatory hurdles, and increases rate of success.

We sought to characterize the antimicrobial properties of five known bioactives (DMAQ-B1, carboplatin, oxaliplatin, CD437 and PSB-069) that were discovered in a high-throughput phenotypic screen for hits that extend survival during exposure to PA14.

c.f.u. assays, biofilm staining and fluorescence microscopy were used to assay the compounds' effect on various virulence determinants. Checkerboard assays were used to assess synergy between compounds and conventional antimicrobials. -based assays were used to test whether the compounds could also rescue against and . Finally, toxicity was assessed in and mammalian cells.

Four of the compounds rescued from a second bacterial pathogen and two of them (DMAQ-B1, a naturally occurring insulin mimetic, and CD437, an agonist of the retinoic acid receptor) rescued against all three. The platinum complexes displayed increased antimicrobial activity against . Of the molecules tested, only CD437 showed slight synergy with ampicillin. The two most effective compounds, DMAQ-B1 and CD437, showed toxicity to mammalian cells.

Although these compounds' potential for repurposing is limited by their toxicity, our results contribute to this growing field and provide a simple road map for using for preliminary testing of known bioactive compounds with predicted antimicrobial activity.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): Antimicrobials , C. elegans , Drug Repositioning and P. aeruginosa
Funding
This study was supported by the:
  • John S. Dunn Foundation
    • Principle Award Recipient: Natalia V Kirienko
  • National Institute of General Medical Sciences (Award T32GM120011)
    • Principle Award Recipient: Nicholas A Hummell
  • Welch Foundation (Award C-1930)
    • Principle Award Recipient: Natalia V Kirienko
  • National Institute of General Medical Sciences (Award R35GM129294)
    • Principle Award Recipient: Natalia V Kirienko
  • Cancer Prevention and Research Institute of Texas (US) (Award RR150044)
    • Principle Award Recipient: Natalia V Kirienko
© 2020 The Authors
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2020-03-12
2024-04-25
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References

  1. Tagliabue A, Rappuoli R. Changing priorities in vaccinology: antibiotic resistance moving to the top. Front Immunol 2018; 9:1068 [View Article][PubMed]
     [Google Scholar]
  2. Piddock LJV. The crisis of no new antibiotics--what is the way forward?. Lancet Infect Dis 2012; 12:249–253 [View Article][PubMed]
     [Google Scholar]
  3. DiMasi JA, Grabowski HG, Hansen RW. Innovation in the pharmaceutical industry: New estimates of R&D costs. J Health Econ 2016; 47:20–33 [View Article][PubMed]
     [Google Scholar]
  4. Rajkumar SV. Thalidomide in multiple myeloma. Oncology 2000; 14:11–16[PubMed]
     [Google Scholar]
  5. Choi DS, Blanco E, Kim Y-S, Rodriguez AA, Zhao H et al. Chloroquine eliminates cancer stem cells through deregulation of Jak2 and DNMT1. Stem Cells 2014; 32:2309–2323 [View Article][PubMed]
     [Google Scholar]
  6. Zappacosta AR. Reversal of baldness in patient receiving minoxidil for hypertension. N Engl J Med 1980; 303:1480–1481 [View Article][PubMed]
     [Google Scholar]
  7. Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S et al. Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov 2019; 18:41–58 [View Article][PubMed]
     [Google Scholar]
  8. Chong CR, Sullivan DJ. New uses for old drugs. Nature 2007; 448:645–646 [View Article][PubMed]
     [Google Scholar]
  9. Konstan MW, Vargo KM, Davis PB. Ibuprofen attenuates the inflammatory response to Pseudomonas aeruginosa in a rat model of chronic pulmonary infection. Implications for antiinflammatory therapy in cystic fibrosis. Am Rev Respir Dis 1990; 141:186–192 [View Article][PubMed]
     [Google Scholar]
  10. Shah PN, Marshall-Batty KR, Smolen JA, Tagaev JA, Chen Q et al. Antimicrobial activity of ibuprofen against cystic fibrosis-associated gram-negative pathogens. Antimicrob Agents Chemother 2018; 62: 23 02 2018 [View Article][PubMed]
     [Google Scholar]
  11. Kinnings SL, Liu N, Buchmeier N, Tonge PJ, Xie L et al. Drug discovery using chemical systems biology: repositioning the safe medicine Comtan to treat multi-drug and extensively drug resistant tuberculosis. PLoS Comput Biol 2009; 5:e1000423 [View Article][PubMed]
     [Google Scholar]
  12. Martinez JL, Sánchez MB, Martínez-Solano L, Hernandez A, Garmendia L et al. Functional role of bacterial multidrug efflux pumps in microbial natural ecosystems. FEMS Microbiol Rev 2009; 33:430–449 [View Article][PubMed]
     [Google Scholar]
  13. Poole K. Resistance to beta-lactam antibiotics. Cell Mol Life Sci 2004; 61:2200–2223 [View Article][PubMed]
     [Google Scholar]
  14. Lerminiaux NA, Cameron ADS. Horizontal transfer of antibiotic resistance genes in clinical environments. Can J Microbiol 2019; 65:34–44 [View Article][PubMed]
     [Google Scholar]
  15. Clunes MT, Boucher RC. Cystic fibrosis: the mechanisms of pathogenesis of an inherited lung disorder. Drug Discov Today Dis Mech 2007; 4:63–72 [View Article][PubMed]
     [Google Scholar]
  16. Bhagirath AY, Li Y, Somayajula D, Dadashi M, Badr S et al. Cystic fibrosis lung environment and Pseudomonas aeruginosa infection. BMC Pulm Med 2016; 16:174 [View Article][PubMed]
     [Google Scholar]
  17. Cai Y, Cao X, Aballay A. Whole-animal chemical screen identifies colistin as a new immunomodulator that targets conserved pathways. mBio 2014; 5:e01235-14 12 Aug 2014 [View Article][PubMed]
     [Google Scholar]
  18. Rajamuthiah R, Fuchs BB, Jayamani E, Kim Y, Larkins-Ford J et al. Whole animal automated platform for drug discovery against multi-drug resistant Staphylococcus aureus. PLoS One 2014; 9:e89189 [View Article][PubMed]
     [Google Scholar]
  19. Moy TI, Conery AL, Larkins-Ford J, Wu G, Mazitschek R et al. High-Throughput screen for novel antimicrobials using a whole animal infection model. ACS Chem Biol 2009; 4:527–533 [View Article][PubMed]
     [Google Scholar]
  20. Pukkila-Worley R, Feinbaum R, Kirienko NV, Larkins-Ford J, Conery AL et al. Stimulation of host immune defenses by a small molecule protects C. elegans from bacterial infection. PLoS Genet 2012; 8:e1002733 [View Article][PubMed]
     [Google Scholar]
  21. Kim W, Zhu W, Hendricks GL, Van Tyne D, Steele AD et al. A new class of synthetic retinoid antibiotics effective against bacterial persisters. Nature 2018; 556:103–107 [View Article][PubMed]
     [Google Scholar]
  22. Kirienko DR, Revtovich AV, Kirienko NV. A high-content, phenotypic screen identifies Fluorouridine as an inhibitor of pyoverdine biosynthesis and Pseudomonas aeruginosa virulence. mSphere 2016; 1: 24 08 2016 [View Article][PubMed]
     [Google Scholar]
  23. Kirienko DR, Kang D, Kirienko NV. Novel Pyoverdine Inhibitors Mitigate Pseudomonas aeruginosa Pathogenesis. Front Microbiol 2018; 9:3317 [View Article][PubMed]
     [Google Scholar]
  24. Salituro GM, Pelaez F, Zhang BB. Discovery of a small molecule insulin receptor activator. Recent Prog Horm Res 2001; 56:107–126 [View Article][PubMed]
     [Google Scholar]
  25. Han T, Goralski M, Capota E, Padrick SB, Kim J et al. The antitumor toxin CD437 is a direct inhibitor of DNA polymerase α. Nat Chem Biol 2016; 12:511–515 [View Article][PubMed]
     [Google Scholar]
  26. Leiting JL, Grotz TE. Advancements and challenges in treating advanced gastric cancer in the West. World J Gastrointest Oncol 2019; 11:652–664 [View Article][PubMed]
     [Google Scholar]
  27. Quintão NLM, Santin JR, Stoeberl LC, Corrêa TP, Melato J et al. Pharmacological treatment of chemotherapy-induced neuropathic pain: PPARγ agonists as a promising tool. Front Neurosci 2019; 13:907 [View Article][PubMed]
     [Google Scholar]
  28. Baqi Y, Weyler S, Iqbal J, Zimmermann H, Müller CE. Structure-Activity relationships of anthraquinone derivatives derived from bromaminic acid as inhibitors of ectonucleoside triphosphate diphosphohydrolases (E-NTPDases). Purinergic Signal 2009; 5:91–106 [View Article][PubMed]
     [Google Scholar]
  29. Moy TI, Ball AR, Anklesaria Z, Casadei G, Lewis K et al. Identification of novel antimicrobials using a live-animal infection model. Proc Natl Acad Sci U S A 2006; 103:10414–10419 [View Article][PubMed]
     [Google Scholar]
  30. Anderson QL, Revtovich AV, Kirienko NV. A high-throughput, high-content, liquid-based C. elegans Pathosystem. J Vis Exp 2018 01 07 2018 [View Article][PubMed]
     [Google Scholar]
  31. NCCLS Methods for Determining Bactericidal Activity of Antimicrobial Agents: Approved Guideline M26-A Wayne, PA: National Committee for Clinical Laboratory Standards; 1999
     [Google Scholar]
  32. Silva F, Lourenço O, Queiroz JA, Domingues FC. Bacteriostatic versus bactericidal activity of ciprofloxacin in Escherichia coli assessed by flow cytometry using a novel far-red dye. J Antibiot 2011; 64:321–325 [View Article][PubMed]
     [Google Scholar]
  33. Pankey GA, Sabath LD. Clinical relevance of bacteriostatic versus bactericidal mechanisms of action in the treatment of gram-positive bacterial infections. Clin Infect Dis 2004; 38:864–870 [View Article][PubMed]
     [Google Scholar]
  34. Zadrazilova I, Pospisilova S, Pauk K, Imramovsky A, Vinsova J et al. In vitro bactericidal activity of 4- and 5-chloro-2-hydroxy-N-[1-oxo-1-(phenylamino)alkan-2-yl]benzamides against MRSA. Biomed Res Int 2015; 2015:349534 [View Article][PubMed]
     [Google Scholar]
  35. Belley A, Neesham-Grenon E, Arhin FF, McKay GA, Parr TR et al. Assessment by time-kill methodology of the synergistic effects of oritavancin in combination with other antimicrobial agents against Staphylococcus aureus. Antimicrob Agents Chemother 2008; 52:3820–3822 [View Article][PubMed]
     [Google Scholar]
  36. Kang D, Kirienko DR, Webster P, Fisher AL, Kirienko NV. Pyoverdine, a siderophore from Pseudomonas aeruginosa, translocates into C. elegans, removes iron, and activates a distinct host response. Virulence 2018; 9:804–817 [View Article][PubMed]
     [Google Scholar]
  37. Kirienko NV, Kirienko DR, Larkins-Ford J, Wählby C, Ruvkun G et al. Pseudomonas aeruginosa disrupts Caenorhabditis elegans iron homeostasis, causing a hypoxic response and death. Cell Host Microbe 2013; 13:406–416 [View Article][PubMed]
     [Google Scholar]
  38. Tjahjono E, Kirienko NV. A conserved mitochondrial surveillance pathway is required for defense against Pseudomonas aeruginosa . PLoS Genet 2017; 13:e1006876 [View Article][PubMed]
     [Google Scholar]
  39. Kang D, Revtovich AV, Chen Q, Shah KN, Cannon CL et al. Pyoverdine-Dependent Virulence of Pseudomonas aeruginosa Isolates From Cystic Fibrosis Patients. Front Microbiol 2019; 10:2048 [View Article][PubMed]
     [Google Scholar]
  40. Zou C-G, Tu Q, Niu J, Ji X-L, Zhang K-Q. The DAF-16/FoxO transcription factor functions as a regulator of epidermal innate immunity. PLoS Pathog 2013; 9:e1003660 [View Article][PubMed]
     [Google Scholar]
  41. Papp D, Csermely P, Sőti C. A role for SKN-1/Nrf in pathogen resistance and immunosenescence in Caenorhabditis elegans . PLoS Pathog 2012; 8:e1002673 [View Article][PubMed]
     [Google Scholar]
  42. Kim DH, Feinbaum R, Alloing G, Emerson FE, Garsin DA et al. A conserved p38 MAP kinase pathway in Caenorhabditis elegans innate immunity. Science 2002; 297:623–626 [View Article][PubMed]
     [Google Scholar]
  43. Høiby N, Ciofu O, Bjarnsholt T. Pseudomonas aeruginosa biofilms in cystic fibrosis. Future Microbiol 2010; 5:1663–1674 [View Article][PubMed]
     [Google Scholar]
  44. Stewart PS. Mechanisms of antibiotic resistance in bacterial biofilms. Int J Med Microbiol 2002; 292:107–113 [View Article][PubMed]
     [Google Scholar]
  45. Lebeaux D, Ghigo J-M, Beloin C. Biofilm-related infections: bridging the gap between clinical management and fundamental aspects of recalcitrance toward antibiotics. Microbiol Mol Biol Rev 2014; 78:510–543 [View Article][PubMed]
     [Google Scholar]
  46. Parrino B, Schillaci D, Carnevale I, Giovannetti E, Diana P et al. Synthetic small molecules as Anti-Biofilm agents in the struggle against antibiotic resistance. Eur J Med Chem 2019; 161:154–178 [View Article][PubMed]
     [Google Scholar]
  47. Revtovich AV, Lee R, Kirienko NV. Interplay between mitochondria and diet mediates pathogen and stress resistance in Caenorhabditis elegans . PLoS Genet 2019; 15:e1008011 [View Article][PubMed]
     [Google Scholar]
  48. De Haan EJ, Charles R. The mechanism of uncoupling of oxidative phosphorylation by 2-methyl-1,4-naphthoquinone. Biochim Biophys Acta 1969; 180:417–419 [View Article][PubMed]
     [Google Scholar]
  49. Munday R, Smith BL, Fowke EA. Haemolytic activity and nephrotoxicity of 2-hydroxy-1,4-naphthoquinone in rats. J Appl Toxicol 1991; 11:85–90 [View Article][PubMed]
     [Google Scholar]
  50. Chesis PL, Levin DE, Smith MT, Ernster L, Ames BN. Mutagenicity of quinones: pathways of metabolic activation and detoxification. Proc Natl Acad Sci U S A 1984; 81:1696–1700 [View Article][PubMed]
     [Google Scholar]
  51. Strowski MZ, Li Z, Szalkowski D, Shen X, Guan X-M et al. Small-Molecule insulin mimetic reduces hyperglycemia and obesity in a nongenetic mouse model of type 2 diabetes. Endocrinology 2004; 145:5259–5268 [View Article][PubMed]
     [Google Scholar]
  52. Zhang B, Salituro G, Szalkowski D, Li Z, Zhang Y et al. Discovery of a small molecule insulin mimetic with antidiabetic activity in mice. Science 1999; 284:974–977 [View Article][PubMed]
     [Google Scholar]
  53. Qureshi SA, Ding V, Li Z, Szalkowski D, Biazzo-Ashnault DE et al. Activation of insulin signal transduction pathway and anti-diabetic activity of small molecule insulin receptor activators. J Biol Chem 2000; 275:36590–36595 [View Article][PubMed]
     [Google Scholar]
  54. Tsai HJ, Chou S-Y. A novel hydroxyfuroic acid compound as an insulin receptor activator. structure and activity relationship of a prenylindole moiety to insulin receptor activation. J Biomed Sci 2009; 16:68 [View Article][PubMed]
     [Google Scholar]
  55. Sundar L, Chang FN. Antimicrobial activity and biosynthesis of indole antibiotics produced by Xenorhabdus nematophilus. J Gen Microbiol 1993; 139:3139–3148 [View Article][PubMed]
     [Google Scholar]
  56. Lown JW. The mechanism of action of quinone antibiotics. Mol Cell Biochem 1983; 55:17–40 [View Article][PubMed]
     [Google Scholar]
  57. Johnstone TC, Park GY, Lippard SJ. Understanding and improving platinum anticancer drugs--phenanthriplatin. Anticancer Res 2014; 34:471–476[PubMed]
     [Google Scholar]
  58. Joyce K, Saxena S, Williams A, Damurjian C, Auricchio N et al. Antimicrobial spectrum of the antitumor agent, cisplatin. J Antibiot 2010; 63:530–532 [View Article][PubMed]
     [Google Scholar]
  59. Yuan M, Chua SL, Liu Y, Drautz-Moses DI, Yam JKH et al. Repurposing the anticancer drug cisplatin with the aim of developing novel Pseudomonas aeruginosa infection control agents. Beilstein J Org Chem 2018; 14:3059–3069 [View Article][PubMed]
     [Google Scholar]
  60. Shinagawa H. Sos response as an adaptive response to DNA damage in prokaryotes. EXS 1996; 77:221–235 [View Article][PubMed]
     [Google Scholar]
  61. Jennerwein MM, Eastman A, Khokhar A. Characterization of adducts produced in DNA by isomeric 1,2-diaminocyclohexaneplatinum(II) complexes. Chem Biol Interact 1989; 70:39–49 [View Article][PubMed]
     [Google Scholar]
  62. Kang D, Kirienko NV. High-Throughput genetic screen reveals that early attachment and biofilm formation are necessary for full pyoverdine production by Pseudomonas aeruginosa . Front Microbiol 2017; 8:1707 [View Article][PubMed]
     [Google Scholar]
  63. Stiernagle T. Maintenance of C. elegans . WormBook 20061–11 [View Article][PubMed]
     [Google Scholar]
  64. Beanan MJ, Strome S. Characterization of a germ-line proliferation mutation in C. elegans . Development 1992; 116:755–766[PubMed]
     [Google Scholar]
  65. Bolz DD, Tenor JL, Aballay A. A conserved PMK-1/p38 MAPK is required in Caenorhabditis elegans tissue-specific immune response to Yersinia pestis infection. J Biol Chem 2010; 285:10832–10840 [View Article][PubMed]
     [Google Scholar]
  66. Link CD, Johnson CJ. Reporter transgenes for study of oxidant stress in Caenorhabditis elegans . Methods Enzymol 2002; 353:497–505 [View Article][PubMed]
     [Google Scholar]
  67. Henderson ST, Johnson TE. Daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans . Curr Biol 2001; 11:1975–1980 [View Article][PubMed]
     [Google Scholar]
  68. Kirienko NV, Fay DS. SLR-2 and JMJC-1 regulate an evolutionarily conserved stress-response network. EMBO J 2010; 29:727–739 [View Article][PubMed]
     [Google Scholar]
  69. Schroth MN, Cho JJ, Green SK, Kominos SD. D. J Med Microbiol 2018; 67:1191–1201 [View Article][PubMed]
     [Google Scholar]
  70. Beabout K, McCurry MD, Mehta H, Shah AA, Pulukuri KK et al. Experimental evolution of diverse strains as a method for the determination of biochemical mechanisms of action for novel Pyrrolizidinone antibiotics. ACS Infect Dis 2017; 3:854–865 [View Article][PubMed]
     [Google Scholar]
  71. Garsin DA, Sifri CD, Mylonakis E, Qin X, Singh KV et al. A simple model host for identifying gram-positive virulence factors. Proc Natl Acad Sci U S A 2001; 98:10892–10897 [View Article][PubMed]
     [Google Scholar]
  72. Merritt JH, Kadouri DE, O'Toole GA. Growing and analyzing static biofilms. Curr Protoc Microbiol 2005; Chapter 1:Unit 1B.1 [View Article][PubMed]
     [Google Scholar]
  73. Hall MJ, Middleton RF, Westmacott D. The fractional inhibitory concentration (Fic) index as a measure of synergy. J Antimicrob Chemother 1983; 11:427–433 [View Article][PubMed]
     [Google Scholar]
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Repurposing bioactive compounds for treating multidrug-resistant pathogens
J. Med. Microbiol. 69, 881 (2020); https://doi.org/10.1099/jmm.0.001172
/content/journal/jmm/10.1099/jmm.0.001172
/content/journal/jmm/10.1099/jmm.0.001172
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