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Antimicrobial agents and chemotherapy
11 17, 2021;65 (12): e0154521.

Activity of Bedaquiline and Imipenem against Actively Growing, Nutrient-Starved, and Intracellular Mycobacterium abscessus.

Olumide Martins, Jin Lee, Amit Kaushik, Nicole C Ammerman, Kelly E Dooley, Eric L Nuermberger
Author Information
  1. Olumide Martins: Center for Tuberculosis Research, Department of Medicine, Johns Hopkins Universitygrid.21107.35grid.471401.7grid.21107.35 School of Medicine, Baltimore, Maryland, USA.
  2. Jin Lee: Center for Tuberculosis Research, Department of Medicine, Johns Hopkins Universitygrid.21107.35grid.471401.7grid.21107.35 School of Medicine, Baltimore, Maryland, USA.
  3. Amit Kaushik: Center for Tuberculosis Research, Department of Medicine, Johns Hopkins Universitygrid.21107.35grid.471401.7grid.21107.35 School of Medicine, Baltimore, Maryland, USA. ORCID
  4. Nicole C Ammerman: Center for Tuberculosis Research, Department of Medicine, Johns Hopkins Universitygrid.21107.35grid.471401.7grid.21107.35 School of Medicine, Baltimore, Maryland, USA. ORCID
  5. Kelly E Dooley: Center for Tuberculosis Research, Department of Medicine, Johns Hopkins Universitygrid.21107.35grid.471401.7grid.21107.35 School of Medicine, Baltimore, Maryland, USA. ORCID
  6. Eric L Nuermberger: Center for Tuberculosis Research, Department of Medicine, Johns Hopkins Universitygrid.21107.35grid.471401.7grid.21107.35 School of Medicine, Baltimore, Maryland, USA. ORCID
PMID: 34516254 DOI: 10.1128/AAC.01545-21

Abstract

Mycobacterium abscessus lung disease is difficult to treat due to intrinsic drug resistance and the persistence of drug-tolerant bacteria. Currently, the standard of care is a multidrug regimen with at least 3 active drugs, preferably including a β-lactam (imipenem or cefoxitin). These regimens are lengthy and toxic and have limited efficacy. The search for more efficacious regimens led us to evaluate Bedaquiline, a diarylquinoline licensed for treatment of multidrug-resistant tuberculosis. We performed time-kill experiments to evaluate the activity of Bedaquiline alone and in combination with the first-line drug imipenem against M. abscessus under various conditions. Against actively growing bacteria, Bedaquiline was largely bacteriostatic and antagonized the bactericidal activity of imipenem. Contrarily, against nutrient-starved persisters, Bedaquiline was bactericidal, while imipenem was not, and Bedaquiline drove the activity of the combination. In an intracellular infection model, Bedaquiline and imipenem had additive bactericidal effects. Correlations between ATP levels and the bactericidal activity of imipenem and its antagonism by Bedaquiline were observed. Interestingly, the presence of Tween 80 in the media affected the activity of both drugs, enhancing the activity of imipenem and reducing that of Bedaquiline. Overall, these results show that Bedaquiline and imipenem interact differently depending on culture conditions. Previously reported antagonistic effects of Bedaquiline on imipenem were limited to conditions with actively multiplying bacteria and/or the presence of Tween 80, whereas the combination was additive or indifferent against nutrient-starved and intracellular M. abscessus, where promising bactericidal activity of the combination suggests it may have a role in future treatment regimens.

Keywords

Mycobacterium abscessus bedaquiline imipenem

References

  1. Antimicrob Agents Chemother. 2018 Jul 27;62(8): [PMID: 29866869]
  2. Am J Respir Crit Care Med. 2003 May 15;167(10):1348-54 [PMID: 12519740]
  3. Antimicrob Agents Chemother. 2019 Mar 27;63(4): [PMID: 30745387]
  4. Eur Respir J. 2020 Jul 7;56(1): [PMID: 32636299]
  5. Antimicrob Agents Chemother. 2019 Jul 25;63(8): [PMID: 31182531]
  6. Am Rev Tuberc. 1947 Oct;56(4):334-45 [PMID: 20270481]
  7. J Infect Chemother. 2016 May;22(5):346-9 [PMID: 26809218]
  8. J Bacteriol. 1948 Aug;56(2):245-52 [PMID: 16561566]
  9. Future Microbiol. 2017 May;12:473-480 [PMID: 28326811]
  10. Antimicrob Agents Chemother. 2015 Nov;59(11):6904-12 [PMID: 26303795]
  11. J Bacteriol. 2007 Jun;189(11):4153-60 [PMID: 17416658]
  12. J Infect Dis. 2014 Mar;209(6):905-12 [PMID: 24253289]
  13. J Exp Med. 1956 Nov 1;104(5):763-802 [PMID: 13367342]
  14. Antimicrob Agents Chemother. 2011 Dec;55(12):5485-92 [PMID: 21930883]
  15. Antimicrob Agents Chemother. 2020 Apr 21;64(5): [PMID: 32041716]
  16. J Exp Med. 1948 Jul;88(1):81-8 [PMID: 18871880]
  17. Antimicrob Agents Chemother. 2019 Jan 29;63(2): [PMID: 30509936]
  18. Front Microbiol. 2018 Oct 10;9:2417 [PMID: 30364170]
  19. Sci Rep. 2016 Feb 23;6:21624 [PMID: 26902658]
  20. Antimicrob Agents Chemother. 2009 Oct;53(10):4178-84 [PMID: 19620331]
  21. Antimicrob Agents Chemother. 2017 Oct 24;61(11): [PMID: 28807917]
  22. Antimicrob Agents Chemother. 2020 May 21;64(6): [PMID: 32253217]
  23. Antimicrob Agents Chemother. 2019 Jul 25;63(8): [PMID: 31109979]
  24. Antimicrob Agents Chemother. 2012 Mar;56(3):1444-51 [PMID: 22155815]
  25. Antimicrob Agents Chemother. 2018 Dec 21;63(1): [PMID: 30323043]
  26. Clin Chest Med. 2015 Mar;36(1):67-78 [PMID: 25676520]
  27. Antimicrob Agents Chemother. 2018 Jun 26;62(7): [PMID: 29712658]
  28. Med Mal Infect. 2016 Jun;46(4):220-5 [PMID: 27210281]
  29. J Antimicrob Chemother. 2015 Apr;70(4):1051-8 [PMID: 25525201]
  30. Curr Protoc Microbiol. 2010 Aug;Chapter 10:Unit 10D.1 [PMID: 20812213]
  31. J Antimicrob Chemother. 2019 Apr 1;74(4):935-943 [PMID: 30649327]
  32. Front Microbiol. 2018 Aug 15;9:1898 [PMID: 30158918]
  33. Bioorg Med Chem. 2017 Jul 15;25(14):3746-3755 [PMID: 28545813]
  34. Antimicrob Agents Chemother. 2016 Jul 22;60(8):4590-9 [PMID: 27185800]
  35. Antimicrob Agents Chemother. 2019 Feb 26;63(3): [PMID: 30642937]
  36. Antimicrob Agents Chemother. 2021 Jan 20;65(2): [PMID: 33168614]
  37. J Biol Chem. 2019 Feb 8;294(6):1936-1943 [PMID: 30530783]
  38. Emerg Infect Dis. 2021 Jan;27(1): [PMID: 33227229]
  39. Antimicrob Agents Chemother. 2019 Feb 26;63(3): [PMID: 30642943]
  40. Euro Surveill. 2013 Oct 24;18(43): [PMID: 24176622]
  41. Am Rev Respir Dis. 1980 Jun;121(6):939-49 [PMID: 6774638]
  42. Diagn Microbiol Infect Dis. 2012 Dec;74(4):412-4 [PMID: 23102558]

Grants

  1. K24 AI150349/NIAID NIH HHS
  2. Research Fellowship Award/Roche Holding | Genentech (Genentech Inc)
  3. /Cystic Fibrosis Foundation (CFF)
  4. R21 AI137814/NIAID NIH HHS
  5. K24-AI150349/HHS | National Institutes of Health (NIH)
  6. R21-AI137814/HHS | National Institutes of Health (NIH)

MeSH Term

Anti-Bacterial Agents
Diarylquinolines
Humans
Imipenem
Microbial Sensitivity Tests
Mycobacterium Infections, Nontuberculous
Mycobacterium abscessus
Nutrients

Chemicals

Anti-Bacterial Agents
Diarylquinolines
Imipenem
bedaquiline
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't
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Word Cloud

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