1887

Abstract

infections are difficult to treat and there is an urgent need for alternative (combination) treatments. The use of anti-virulence therapies in combination with antibiotics is a possible strategy to increase the antimicrobial susceptibility of the pathogen and to slow down the development of resistance. In the present study we evaluated the β-lactam and colistin-potentiating activity, and anti-virulence effect of the non-mevalonate pathway inhibitor FR900098 against in various and models. In addition, we evaluated whether repeated exposure to FR900098 alone or when combined with ceftazidime leads to increased resistance. FR900098 potentiated the activity of colistin and several β-lactam antibiotics (aztreonam, cefepime, cefotaxime, ceftazidime, mecillinam and piperacillin) but not of imipenem and meropenem. When used alone or in combination with ceftazidime, FR900098 increased the survival of infected and . Furthermore, combining ceftazidime with FR900098 resulted in a significant inhibition of the biofilm formation of . Repeated exposure to FR900098 in the infection model did not lead to decreased activity, and the susceptibility of the evolved HI2424 lineages to ceftazidime, FR900098 and the combination of both remained unchanged. In conclusion, FR900098 reduces virulence and potentiates ceftazidime in an model, and this activity is not lost during the experimental evolution experiment carried out in the present study.

Funding
This study was supported by the:
  • Bijzonder Onderzoeksfonds (Award BOF.DOC.2018.0023.01)
    • Principle Award Recipient: MonaBové
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2022-03-31
2024-07-25
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References

  1. Scoffone VC, Chiarelli LR, Trespidi G, Mentasti M, Riccardi G et al. Burkholderia cenocepacia infections in cystic fibrosis patients: drug resistance and therapeutic approaches. Front Microbiol 2017; 8:1592 [View Article] [PubMed]
    [Google Scholar]
  2. Kalferstova L, Kolar M, Fila L, Vavrova J, Drevinek P. Gene expression profiling of Burkholderia cenocepacia at the time of cepacia syndrome: loss of motility as a marker of poor prognosis?. J Clin Microbiol 2015; 53:1515–1522 [View Article] [PubMed]
    [Google Scholar]
  3. Garcia BA, Carden JL, Goodwin DL, Smith TA, Gaggar A et al. Implementation of a successful eradication protocol for Burkholderia Cepacia complex in cystic fibrosis patients. BMC Pulm Med 2018; 18:35 [View Article] [PubMed]
    [Google Scholar]
  4. Tamma PD, Fan Y, Bergman Y, Sick-Samuels AC, Hsu AJ et al. Successful treatment of persistent Burkholderia cepacia complex bacteremia with ceftazidime-avibactam. Antimicrob Agents Chemother 2018; 62:e02213-17 [View Article] [PubMed]
    [Google Scholar]
  5. Narayanaswamy VP, Duncan AP, LiPuma JJ, Wiesmann WP, Baker SM et al. In Vitro Activity of a Novel Glycopolymer against Biofilms of Burkholderia cepacia Complex Cystic Fibrosis Clinical Isolates. Antimicrob Agents Chemother 2019; 63:e00498-19 [View Article] [PubMed]
    [Google Scholar]
  6. Sass A, Everaert A, Van Acker H, Van den Driessche F, Coenye T. Targeting the nonmevalonate pathway in Burkholderia cenocepacia increases susceptibility to certain β-lactam antibiotics. Antimicrob Agents Chemother 2018; 62:e02607-17 [View Article] [PubMed]
    [Google Scholar]
  7. Chofor R, Sooriyaarachchi S, Risseeuw MDP, Bergfors T, Pouyez J et al. Synthesis and bioactivity of β-substituted fosmidomycin analogues targeting 1-deoxy-D-xylulose-5-phosphate reductoisomerase. J Med Chem 2015; 58:2988–3001 [View Article] [PubMed]
    [Google Scholar]
  8. Hui X, Yue Q, Zhang DD, Li H, Yang SQ et al. Antimicrobial mechanism of theaflavins: They target 1-deoxy-D-xylulose 5-phosphate reductoisomerase, the key enzyme of the MEP terpenoid biosynthetic pathway. Sci Rep 2016; 6:1–8 [View Article] [PubMed]
    [Google Scholar]
  9. Schmerk CL, Welander PV, Hamad MA, Bain KL, Bernards MA et al. Elucidation of the Burkholderia cenocepacia hopanoid biosynthesis pathway uncovers functions for conserved proteins in hopanoid-producing bacteria. Environ Microbiol 2015; 17:735–750 [View Article] [PubMed]
    [Google Scholar]
  10. Schmerk CL, Bernards MA, Valvano MA. Hopanoid production is required for low-pH tolerance, antimicrobial resistance, and motility in Burkholderia cenocepacia. J Bacteriol 2011; 193:6712–6723 [View Article] [PubMed]
    [Google Scholar]
  11. O’Rourke PEF, Kalinowska-Tłuścik J, Fyfe PK, Dawson A, Hunter WN. Crystal structures of IspF from Plasmodium falciparum and Burkholderia cenocepacia: comparisons inform antimicrobial drug target assessment. BMC Struct Biol 2014; 14:1 [View Article] [PubMed]
    [Google Scholar]
  12. Sauvage E, Derouaux A, Fraipont C, Joris M, Herman R et al. Crystal structure of penicillin-binding protein 3 (PBP3) from Escherichia coli. PLoS One 2014; 9:98042 [View Article] [PubMed]
    [Google Scholar]
  13. Macheboeuf P, Contreras-Martel C, Job V, Dideberg O, Dessen A. Penicillin binding proteins: key players in bacterial cell cycle and drug resistance processes. FEMS Microbiol Rev 2006; 30:673–691 [View Article] [PubMed]
    [Google Scholar]
  14. Bellini D, Koekemoer L, Newman H, Dowson CG. Novel and improved crystal structures of H. influenzae, E. coli and P. aeruginosa penicillin-binding protein 3 (PBP3) and N. gonorrhoeae PBP2: toward a better understanding of β-lactam target-mediated resistance. J Mol Biol 2019; 431:3501–3519 [View Article]
    [Google Scholar]
  15. Clark ST, Sinha U, Zhang Y, Wang PW, Donaldson SL et al. Penicillin-binding protein 3 is a common adaptive target among Pseudomonas aeruginosa isolates from adult cystic fibrosis patients treated with β-lactams. Int J Antimicrob Agents 2019; 53:620–628 [View Article] [PubMed]
    [Google Scholar]
  16. Chantratita N, Rholl DA, Sim B, Wuthiekanun V, Limmathurotsakul D et al. Antimicrobial resistance to ceftazidime involving loss of penicillin-binding protein 3 in Burkholderia pseudomallei. Proc Natl Acad Sci U S A 2011; 108:17165–17170 [View Article] [PubMed]
    [Google Scholar]
  17. Alm RA, Johnstone MR, Lahiri SD. Characterization of Escherichia coli NDM isolates with decreased susceptibility to aztreonam/avibactam: role of a novel insertion in PBP3. J Antimicrob Chemother 2015; 70:1420–1428 [View Article] [PubMed]
    [Google Scholar]
  18. Messiaen A-S, Verbrugghen T, Declerck C, Ortmann R, Schlitzer M et al. Resistance of the Burkholderia cepacia complex to fosmidomycin and fosmidomycin derivatives. Int J Antimicrob Agents 2011; 38:261–264 [View Article] [PubMed]
    [Google Scholar]
  19. Armstrong CM, Meyers DJ, Imlay LS, Freel Meyers C, Odom AR. Resistance to the antimicrobial agent fosmidomycin and an FR900098 prodrug through mutations in the deoxyxylulose phosphate reductoisomerase gene (dxr). Antimicrob Agents Chemother 2015; 59:5511–5519 [View Article] [PubMed]
    [Google Scholar]
  20. Buroni S, Chiarelli LR. Antivirulence compounds: a future direction to overcome antibiotic resistance?. Future Microbiol 2020; 15:299–301 [View Article] [PubMed]
    [Google Scholar]
  21. The European Committee on Antimicrobial Susceptibility Testing Reading guide for broth microdilution version 3.0; 2021
  22. Stiernagle T. Maintenance of C. elegans. WormBook 20061–11 [View Article]
    [Google Scholar]
  23. Bové M, Coenye T. n.d Supplementary file of ‘The anti-virulence activity of the non-mevalonate pathway inhibitor FR900098 towards burkholderia cenocepacia is maintained during experimental evolution.
  24. Han S, Zaniewski RP, Marr ES, Lacey BM, Tomaras AP et al. Structural basis for effectiveness of siderophore-conjugated monocarbams against clinically relevant strains of Pseudomonas aeruginosa. Proc Natl Acad Sci U S A 2010; 107:22002–22007 [View Article]
    [Google Scholar]
  25. Eberhardt C, Kuerschner L, Weiss DS. Probing the catalytic activity of a cell division-specific transpeptidase in vivo with beta-lactams. J Bacteriol 2003; 185:3726–3734 [View Article] [PubMed]
    [Google Scholar]
  26. Buijs J, Dofferhoff ASM, Mouton JW, Wagenvoort JHT, van der Meer JWM. Concentration-dependency of beta-lactam-induced filament formation in Gram-negative bacteria. Clin Microbiol Infect 2008; 14:344–349 [View Article] [PubMed]
    [Google Scholar]
  27. Sutaria DS, Moya B, Green KB, Kim TH, Tao X et al. First penicillin-binding protein occupancy patterns of β-lactams and β-lactamase inhibitors in Klebsiella pneumoniae. Antimicrob Agents Chemother 2018; 62:e00282-18 [View Article] [PubMed]
    [Google Scholar]
  28. Kocaoglu O, Carlson EE. Profiling of β-lactam selectivity for penicillin-binding proteins in Escherichia coli strain DC2. Antimicrob Agents Chemother 2015; 59:2785–2790 [View Article] [PubMed]
    [Google Scholar]
  29. Nzula S, Vandamme P, Govan JR. Influence of taxonomic status on the in vitro antimicrobial susceptibility of the Burkholderia cepacia complex. J Antimicrob Chemother 2002; 50:265–269 [View Article] [PubMed]
    [Google Scholar]
  30. Leitão JH, Sousa SA, Cunha MV, Salgado MJ, Melo-Cristino J et al. Variation of the antimicrobial susceptibility profiles of Burkholderia cepacia complex clonal isolates obtained from chronically infected cystic fibrosis patients: a five-year survey in the major Portuguese treatment center. Eur J Clin Microbiol Infect Dis 2008; 27:1101–1111 [View Article] [PubMed]
    [Google Scholar]
  31. Malott RJ, Steen-Kinnaird BR, Lee TD, Speert DP. Identification of hopanoid biosynthesis genes involved in polymyxin resistance in Burkholderia multivorans. Antimicrob Agents Chemother 2012; 56:464–471 [View Article] [PubMed]
    [Google Scholar]
  32. Kalynych S, Morona R, Cygler M. Progress in understanding the assembly process of bacterial O-antigen. FEMS Microbiol Rev 2014; 38:1048–1065 [View Article] [PubMed]
    [Google Scholar]
  33. Hamad MA, Di Lorenzo F, Molinaro A, Valvano MA. Aminoarabinose is essential for lipopolysaccharide export and intrinsic antimicrobial peptide resistance in Burkholderia cenocepacia(†). Mol Microbiol 2012; 85:962–974 [View Article] [PubMed]
    [Google Scholar]
  34. Holden MTG, Seth-Smith HMB, Crossman LC, Sebaihia M, Bentley SD et al. The genome of Burkholderia cenocepacia J2315, an epidemic pathogen of cystic fibrosis patients. J Bacteriol 2009; 191:261–277 [View Article] [PubMed]
    [Google Scholar]
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