1887

Journal of Medical Microbiology logo

Volume 66, Issue 3

Novel anti-staphylococcal and anti-biofilm properties of two anti-malarial compounds: MMV665953 {1-(3-chloro-4-fluorophenyl)-3-(3,4-dichlorophenyl)urea} and MMV665807 {5-chloro-2-hydroxy--[3-(trifluoromethyl)phenyl]benzamide} Free

Abstract

The treatment of device-related infections is challenging and current anti-microbial compounds have poor anti-biofilm activity. We aimed to identify and characterize novel compounds effective in the eradication of biofilms.

Two novel compounds, MMV665953 {1-(3-chloro-4-fluorophenyl)-3-(3,4-dichlorophenyl)urea} and MMV665807{5-chloro-2-hydroxy--[3-(trifluoromethyl)phenyl]benzamide}, effective in killing biofilms, were identified by screening of the open access 'malaria box' chemical library. The minimum bactericidal concentrations, half-maximal inhibition concentration (IC) values and minimal biofilm killing concentrations effective in the killing of biofilm were determined against meticillin-resistant and meticillin-sensitive . Fibrin-embedded biofilms were grown under -relevant conditions, and viability was measured using a resazurin-conversion assay and confocal microscopy. The potential for the development of resistance and cytotoxicity was also assessed.

MMV665953 and MMV665807 were bactericidal against isolates. The IC against biofilms was at 0.15–0.58 mg l after 24 h treatment, whereas the concentration required to eradicate all tested biofilms was 4 mg l, making the compounds more bactericidal than conventional antibiotics. The cytotoxicity against human keratinocytes and primary endothelial cells was determined as IC 7.47 and 0.18 mg l for MMV665953, and as 1.895 and 0.076 mg l for MMV665807. Neither compound was haemolytic nor caused platelet activation. MMV665953 and MMV665807 derivatives with reduced cytotoxicity exhibited a concomitant loss in anti-staphylococcal activity.

MMV665953 and MMV665807 are more bactericidal against biofilms than currently used anti-staphylococcal antibiotics and represent a valuable structural basis for further investigation in the treatment of staphylococcal biofilm-related infections.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): biofilm , malaria box , novel antimicrobials and Staphylococcus aureus
© 2017 The Authors
Loading

Article metrics loading...

/content/journal/jmm/10.1099/jmm.0.000446
2017-03-01
2024-04-24
Loading full text...

Full text loading...

/deliver/fulltext/jmm/66/3/377.html?itemId=/content/journal/jmm/10.1099/jmm.0.000446&mimeType=html&fmt=ahah

References

  1. Arciola CR, Visai L, Testoni F, Arciola S, Campoccia D et al. Concise survey of Staphylococcus aureus virulence factors that promote adhesion and damage to peri-implant tissues. Int J Artif Organs 2011; 34:771–780 [View Article][PubMed]
     [Google Scholar]
  2. Montanaro L, Speziale P, Campoccia D, Ravaioli S, Cangini I et al. Scenery of Staphylococcus implant infections in orthopedics. Future Microbiol 2011; 6:1329–1349 [View Article][PubMed]
     [Google Scholar]
  3. O'Gara JP, Humphreys H. Staphylococcus epidermidis biofilms: importance and implications. J Med Microbiol 2001; 50:582–587 [View Article][PubMed]
     [Google Scholar]
  4. Ravaioli S, Selan L, Visai L, Pirini V, Campoccia D et al. Staphylococcus lugdunensis, an aggressive coagulase-negative pathogen not to be underestimated. Int J Artif Organs 2012; 35:742–753 [View Article][PubMed]
     [Google Scholar]
  5. Toba FA, Akashi H, Arrecubieta C, Lowy FD. Role of biofilm in Staphylococcus aureus and Staphylococcus epidermidis ventricular assist device driveline infections. J Thorac Cardiovasc Surg 2011; 141:1259–1264 [View Article][PubMed]
     [Google Scholar]
  6. Francois P, Schrenzel J, Stoerman-Chopard C, Favre H, Herrmann M et al. Identification of plasma proteins adsorbed on hemodialysis tubing that promote Staphylococcus aureus adhesion. J Lab Clin Med 2000; 135:32–42 [View Article][PubMed]
     [Google Scholar]
  7. Zapotoczna M, McCarthy H, Rudkin JK, O'Gara JP, O'Neill E. An essential role for coagulase in Staphylococcus aureus biofilm development reveals new therapeutic possibilities for device-related infections. J Infect Dis 2015; 212:1883–1893 [View Article][PubMed]
     [Google Scholar]
  8. Geoghegan JA, Monk IR, O'Gara JP, Foster TJ. Subdomains N2N3 of fibronectin binding protein A mediate Staphylococcus aureus biofilm formation and adherence to fibrinogen using distinct mechanisms. J Bacteriol 2013; 195:2675–2683 [View Article][PubMed]
     [Google Scholar]
  9. O'Neill E, Humphreys H, O'Gara JP. Carriage of both the fnbA and fnbB genes and growth at 37 °C promote FnBP-mediated biofilm development in meticillin-resistant Staphylococcus aureus clinical isolates. J Med Microbiol 2009; 58:399–402 [View Article][PubMed]
     [Google Scholar]
  10. Vanassche T, Peetermans M, Van Aelst LN, Peetermans WE, Verhaegen J et al. The role of staphylothrombin-mediated fibrin deposition in catheter-related Staphylococcus aureus infections. J Infect Dis 2013; 208:92–100 [View Article][PubMed]
     [Google Scholar]
  11. Laverty G, Gorman SP, Gilmore BF. Biomolecular mechanisms of staphylococcal biofilm formation. Future Microbiol 2013; 8:509–524 [View Article][PubMed]
     [Google Scholar]
  12. Abdelhady W, Bayer AS, Seidl K, Nast CC, Kiedrowski MR et al. Reduced vancomycin susceptibility in an in vitro catheter-related biofilm model correlates with poor therapeutic outcomes in experimental endocarditis due to methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 2013; 57:1447–1454 [View Article][PubMed]
     [Google Scholar]
  13. Olson ME, Ceri H, Morck DW, Buret AG, Read RR. Biofilm bacteria: formation and comparative susceptibility to antibiotics. Can J Vet Res 2002; 66:86–92[PubMed]
     [Google Scholar]
  14. Chuard C, Vaudaux P, Waldvogel FA, Lew DP. Susceptibility of Staphylococcus aureus growing on fibronectin-coated surfaces to bactericidal antibiotics. Antimicrob Agents Chemother 1993; 37:625–632 [View Article][PubMed]
     [Google Scholar]
  15. Gilbert P, Collier PJ, Brown MR. Influence of growth rate on susceptibility to antimicrobial agents: biofilms, cell cycle, dormancy, and stringent response. Antimicrob Agents Chemother 1990; 34:1865–1868 [View Article][PubMed]
     [Google Scholar]
  16. Guggenbichler JP, Berchtold D, Allerberger F, Bonatti H, Hager J et al. In vitro and in vivo effect of antibiotics on catheters colonized by staphylococci. Eur J Clin Microbiol Infect Dis 1992; 11:408–415 [View Article][PubMed]
     [Google Scholar]
  17. Qu Y, Istivan TS, Daley AJ, Rouch DA, Deighton MA. Comparison of various antimicrobial agents as catheter lock solutions: preference for ethanol in eradication of coagulase-negative staphylococcal biofilms. J Med Microbiol 2009; 58:442–450 [View Article][PubMed]
     [Google Scholar]
  18. Raad I, Hanna H, Dvorak T, Chaiban G, Hachem R. Optimal antimicrobial catheter lock solution, using different combinations of minocycline, EDTA, and 25-percent ethanol, rapidly eradicates organisms embedded in biofilm. Antimicrob Agents Chemother 2007; 51:78–83 [View Article][PubMed]
     [Google Scholar]
  19. Spangenberg T, Burrows JN, Kowalczyk P, McDonald S, Wells TN et al. The open access malaria box: a drug discovery catalyst for neglected diseases. PLoS One 2013; 8:e62906 [View Article][PubMed]
     [Google Scholar]
  20. Macielag MJ, Demers JP, Fraga-Spano SA, Hlasta DJ, Johnson SG et al. Substituted salicylanilides as inhibitors of two-component regulatory systems in bacteria. J Med Chem 1998; 41:2939–2945 [View Article][PubMed]
     [Google Scholar]
  21. Guiguemde WA, Shelat AA, Bouck D, Duffy S, Crowther GJ et al. Chemical genetics of Plasmodium falciparum. Nature 2010; 465:311–315 [View Article][PubMed]
     [Google Scholar]
  22. Van Voorhis WC, Adams JH, Adelfio R, Ahyong V, Akabas MH et al. Open source drug discovery with the malaria box compound collection for neglected diseases and beyond. PLoS Pathog 2016; 12:e1005763 [View Article][PubMed]
     [Google Scholar]
  23. Polonio RE, Mermel LA, Paquette GE, Sperry JF. Eradication of biofilm-forming Staphylococcus epidermidis (RP62A) by a combination of sodium salicylate and vancomycin. Antimicrob Agents Chemother 2001; 45:3262–3266 [View Article][PubMed]
     [Google Scholar]
  24. O'Neill E, Pozzi C, Houston P, Smyth D, Humphreys H et al. Association between methicillin susceptibility and biofilm regulation in Staphylococcus aureus isolates from device-related infections. J Clin Microbiol 2007; 45:1379–1388 [View Article][PubMed]
     [Google Scholar]
  25. Robinson DA, Enright MC. Evolutionary models of the emergence of methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 2003; 47:3926–3934 [View Article][PubMed]
     [Google Scholar]
  26. O'Neill E, Pozzi C, Houston P, Humphreys H, Robinson DA et al. A novel Staphylococcus aureus biofilm phenotype mediated by the fibronectin-binding proteins, FnBPA and FnBPB. J Bacteriol 2008; 190:3835–3850 [View Article][PubMed]
     [Google Scholar]
  27. Conlon KM, Humphreys H, O'Gara JP. icaR encodes a transcriptional repressor involved in environmental regulation of ica operon expression and biofilm formation in Staphylococcus epidermidis. J Bacteriol 2002; 184:4400–4408 [View Article][PubMed]
     [Google Scholar]
  28. Stevens NT, Sadovskaya I, Jabbouri S, Sattar T, O'Gara JP et al. Staphylococcus epidermidis polysaccharide intercellular adhesin induces IL-8 expression in human astrocytes via a mechanism involving TLR2. Cell Microbiol 2009; 11:421–432 [View Article][PubMed]
     [Google Scholar]
  29. Moore GE, Glick JL. Perspective of human cell culture. Surg Clin North Am 1967; 47:1315–1324 [View Article][PubMed]
     [Google Scholar]
  30. Andrews JM. BSAC Methods for Antimicrobial Susceptibility Testing; version 9.1 Birmingham: British Society for Antimicrobial Chemotherapy;; 2010 http://bsac.org.uk/wp-content/uploads/2012/02/Version_9.1_March_2010_final-v2
     [Google Scholar]
  31. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 1983; 65:55–63 [View Article][PubMed]
     [Google Scholar]
  32. Chen Y, Vasil AI, Rehaume L, Mant CT, Burns JL et al. Comparison of biophysical and biologic properties of α-helical enantiomeric antimicrobial peptides. Chem Biol Drug Des 2006; 67:162–173 [View Article][PubMed]
     [Google Scholar]
  33. Congreve M, Carr R, Murray C, Jhoti H. A 'rule of three' for fragment-based lead discovery?. Drug Discov Today 2003; 8:876–877 [View Article][PubMed]
     [Google Scholar]
  34. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 1997; 23:3–25 [View Article]
     [Google Scholar]
  35. Otto BR, Verweij-van Vught AM, MacLaren DM. Blood substitutes and infection. Nature 1992; 358:23–24 [View Article][PubMed]
     [Google Scholar]
  36. Kwiecinski J, Peetermans M, Liesenborghs L, Na M, Björnsdottir H et al. Staphylokinase control of Staphylococcus aureus biofilm formation and detachment through host plasminogen activation. J Infect Dis 2016; 213:139–148 [View Article][PubMed]
     [Google Scholar]
  37. Heilmann C, Schweitzer O, Gerke C, Vanittanakom N, Mack D et al. Molecular basis of intercellular adhesion in the biofilm-forming Staphylococcus epidermidis. Mol Microbiol 1996; 20:1083–1091 [View Article][PubMed]
     [Google Scholar]
  38. Mermel LA, Allon M, Bouza E, Craven DE, Flynn P et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 2009; 49:1–45 [View Article][PubMed]
     [Google Scholar]
  39. Hogan S, Zapotoczna M, Stevens NT, Humphreys H, O'Gara JP et al. In vitro approach for identification of the most effective agents for antimicrobial lock therapy in the treatment of intravascular catheter-related infections caused by Staphylococcus aureus. Antimicrob Agents Chemother 2016; 60:2923–2931 [View Article][PubMed]
     [Google Scholar]
  40. Kahan FM, Kahan JS, Cassidy PJ, Kropp H. The mechanism of action of fosfomycin (phosphonomycin). Ann N Y Acad Sci 1974; 235:364–386 [View Article][PubMed]
     [Google Scholar]
  41. Blake KL, O'Neill AJ, Mengin-Lecreulx D, Henderson PJ, Bostock JM et al. The nature of Staphylococcus aureus MurA and MurZ and approaches for detection of peptidoglycan biosynthesis inhibitors. Mol Microbiol 2009; 72:335–343 [View Article][PubMed]
     [Google Scholar]
  42. Nitanai Y, Kikuchi T, Kakoi K, Hanamaki S, Fujisawa I et al. Crystal structures of the complexes between vancomycin and cell-wall precursor analogs. J Mol Biol 2009; 385:1422–1432 [View Article][PubMed]
     [Google Scholar]
  43. Mollaghan A, Vinsova J, Imramovsky A, Cotter L, Lucey B et al. Antistaphylococcal activity of novel salicylanilide derivatives. Curr Drug Discov Technol 2012; 9:39–47 [View Article][PubMed]
     [Google Scholar]
  44. Lee IY, Gruber TD, Samuels A, Yun M, Nam B et al. Structure-activity relationships of antitubercular salicylanilides consistent with disruption of the proton gradient via proton shuttling. Bioorg Med Chem 2013; 21:114–126 [View Article][PubMed]
     [Google Scholar]
  45. Rajamuthiah R, Fuchs BB, Conery AL, Kim W, Jayamani E et al. Repurposing salicylanilide anthelmintic drugs to combat drug resistant Staphylococcus aureus. PLoS One 2015; 10:e0124595 [View Article][PubMed]
     [Google Scholar]
  46. Krátký M, Vinšová J, Novotná E, Mandíková J, Wsól V et al. Salicylanilide derivatives block Mycobacterium tuberculosis through inhibition of isocitrate lyase and methionine aminopeptidase. Tuberculosis 2012; 92:434–439 [View Article][PubMed]
     [Google Scholar]
  47. Kang S, Min HJ, Kang MS, Jung MG, Kim S. Discovery of novel 2-hydroxydiarylamide derivatives as TMPRSS4 inhibitors. Bioorg Med Chem Lett 2013; 23:1748–1751 [View Article][PubMed]
     [Google Scholar]
  48. Cheng TJ, Wu YT, Yang ST, Lo KH, Chen SK et al. High-throughput identification of antibacterials against methicillin-resistant Staphylococcus aureus (MRSA) and the transglycosylase. Bioorg Med Chem 2010; 18:8512–8529 [View Article][PubMed]
     [Google Scholar]
  49. Dahlgren MK, Kauppi AM, Olsson IM, Linusson A, Elofsson M. Design, synthesis, and multivariate quantitative structure-activity relationship of salicylanilides – potent inhibitors of type III secretion in Yersinia. J Med Chem 2007; 50:6177–6188 [View Article][PubMed]
     [Google Scholar]
  50. Brown ME, Fitzner JN, Stevens T, Chin W, Wright CD et al. Salicylanilides: selective inhibitors of interleukin-12p40 production. Bioorg Med Chem 2008; 16:8760–8764 [View Article][PubMed]
     [Google Scholar]
  51. Liechti C, Séquin U, Bold G, Furet P, Meyer T et al. Salicylanilides as inhibitors of the protein tyrosine kinase epidermal growth factor receptor. Eur J Med Chem 2004; 39:11–26 [View Article][PubMed]
     [Google Scholar]
  52. Terada H, Goto S, Yamamoto K, Takeuchi I, Hamada Y et al. Structural requirements of salicylanilides for uncoupling activity in mitochondria: quantitative analysis of structure-uncoupling relationships. Biochim Biophys Acta 1988; 936:504–512 [View Article][PubMed]
     [Google Scholar]
  53. Liu S, Chang JS, Herberg JT, Horng MM, Tomich PK et al. Allosteric inhibition of Staphylococcus aureus D-alanine:D-alanine ligase revealed by crystallographic studies. Proc Natl Acad Sci USA 2006; 103:15178–15183 [View Article][PubMed]
     [Google Scholar]
  54. Meziane-Cherif D, Saul FA, Moubareck C, Weber P, Haouz A et al. Molecular basis of vancomycin dependence in VanA-type Staphylococcus aureus VRSA-9. J Bacteriol 2010; 192:5465–5471 [View Article][PubMed]
     [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jmm/10.1099/jmm.0.000446
Loading
Novel anti-staphylococcal and anti-biofilm properties of two anti-malarial compounds: MMV665953 {1-(3-chloro-4-fluorophenyl)-3-(3,4-dichlorophenyl)urea} and MMV665807 {5-chloro-2-hydroxy-N-[3-(trifluoromethyl)phenyl]benzamide}
J. Med. Microbiol. 66, 377 (2017); https://doi.org/10.1099/jmm.0.000446
/content/journal/jmm/10.1099/jmm.0.000446
/content/journal/jmm/10.1099/jmm.0.000446
Loading

Data & Media loading...

Supplements

Supplementary File 1

PDF

Most cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error