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Antimicrobial agents and chemotherapy
10 18, 2023;67 (10): e0005123.

A small-molecule membrane fluidizer re-sensitizes methicillin-resistant (MRSA) to β-lactam antibiotics.

Jessica D Podoll, Emma Rosen, Wei Wang, Yuefeng Gao, Jing Zhang, Xiang Wang
Author Information
  1. Jessica D Podoll: Recreo Pharmaceuticals Inc, Yale Circle , Boulder, Colorado, USA.
  2. Emma Rosen: Recreo Pharmaceuticals Inc, Yale Circle , Boulder, Colorado, USA.
  3. Wei Wang: Department of Chemistry, University of Colorado , Boulder, Colorado, USA.
  4. Yuefeng Gao: Department of Chemistry, University of Colorado , Boulder, Colorado, USA.
  5. Jing Zhang: Recreo Pharmaceuticals Inc, Yale Circle , Boulder, Colorado, USA.
  6. Xiang Wang: Department of Chemistry, University of Colorado , Boulder, Colorado, USA. ORCID
PMID: 37681969 DOI: 10.1128/aac.00051-23

Abstract

Novel antibacterial agents and strategies are urgently needed to fight against the ongoing global antibiotic resistance problem. While natural products remain the main source in antibiotic discovery, synthetic antibacterials provide an attractive alternative and may evade the ancient antibiotic resistance. Herein, we report a small molecule that re-sensitizes methicillin-resistant to β-lactam antibiotics with extremely low potential for resistance development. It belongs to a new class of broad-spectrum antibacterials, trypyricins, which share similar structural characteristics and mechanism of action to the cationic antimicrobial peptides. Mechanistic studies indicated that trypyricins fluidize and disrupt bacterial cytoplasmic membrane. These results suggested that trypyricins represent a promising new class of antibacterials and may be further developed as antibiotic adjuvants to fight against resistant bacteria in the clinic.

Keywords

antibiotic antibiotic adjuvant antimicrobial resistance membrane fluidizer

References

  1. Cell Microbiol. 2004 Mar;6(3):269-75 [PMID: 14764110]
  2. PLoS One. 2016 May 11;11(5):e0155139 [PMID: 27167126]
  3. Cell. 2017 Nov 30;171(6):1354-1367.e20 [PMID: 29103614]
  4. PLoS One. 2017 Jul 31;12(7):e0181748 [PMID: 28759605]
  5. Antimicrob Agents Chemother. 2008 Oct;52(10):3820-2 [PMID: 18644953]
  6. Int J Antimicrob Agents. 2016 Dec;48(6):607-613 [PMID: 27865626]
  7. Antimicrob Agents Chemother. 1996 Aug;40(8):1914-8 [PMID: 8843303]
  8. J Antimicrob Chemother. 2008 Nov;62(5):1003-8 [PMID: 18669516]
  9. Clin Infect Dis. 2004 Mar 15;38(6):864-70 [PMID: 14999632]
  10. Nat Rev Microbiol. 2019 Apr;17(4):203-218 [PMID: 30737488]
  11. Proc Natl Acad Sci U S A. 2013 Oct 1;110(40):16169-74 [PMID: 24046367]
  12. FEMS Microbiol Rev. 2019 Sep 1;43(5):490-516 [PMID: 31150547]
  13. Antimicrob Agents Chemother. 2012 Oct;56(10):5296-302 [PMID: 22869564]
  14. Int J Med Microbiol. 2019 Jul;309(5):359-363 [PMID: 31182276]
  15. Nat Prod Rep. 2016 May 4;33(5):668-80 [PMID: 26806527]
  16. Microbiology (Reading). 2003 Oct;149(Pt 10):2719-2732 [PMID: 14523105]
  17. Antimicrob Agents Chemother. 2014 Jun;58(6):3008-12 [PMID: 24614373]
  18. Methods Mol Biol. 2017;1520:159-174 [PMID: 27873252]
  19. Lancet Infect Dis. 2013 Dec;13(12):1057-98 [PMID: 24252483]
  20. J Biol Chem. 2005 Sep 16;280(37):32493-8 [PMID: 16020541]
  21. J Antimicrob Chemother. 2021 Sep 15;76(10):2622-2628 [PMID: 34223628]
  22. PLoS Pathog. 2018 Feb 16;14(2):e1006876 [PMID: 29451901]
  23. Biochim Biophys Acta. 2007 Oct;1768(10):2500-9 [PMID: 17599802]
  24. Antimicrob Agents Chemother. 2013 Aug;57(8):3593-600 [PMID: 23689707]
  25. Nature. 2018 Apr 5;556(7699):103-107 [PMID: 29590091]
  26. Antimicrob Agents Chemother. 2021 Jul 16;65(8):e0035621 [PMID: 34097478]
  27. Nucleic Acids Res. 2016 Jan 4;44(D1):D1087-93 [PMID: 26602694]
  28. Trends Microbiol. 2019 Jan;27(1):26-38 [PMID: 30031590]
  29. Sci Rep. 2017 Mar 09;7:44332 [PMID: 28276520]
  30. Science. 2021 Jul 30;373(6554):471 [PMID: 34326211]
  31. Antimicrob Agents Chemother. 2005 Mar;49(3):1127-34 [PMID: 15728913]
  32. Antimicrob Agents Chemother. 2017 Apr 24;61(5): [PMID: 28193654]
  33. Nature. 2011 Aug 31;477(7365):457-61 [PMID: 21881561]
  34. Chem Biol. 2013 Sep 19;20(9):1168-78 [PMID: 23972939]
  35. Antibiotics (Basel). 2020 Jan 13;9(1): [PMID: 31941022]
  36. Front Cell Infect Microbiol. 2016 Dec 27;6:194 [PMID: 28083516]
  37. J Biomol Screen. 2013 Oct;18(9):1018-26 [PMID: 23686103]
  38. Proc Natl Acad Sci U S A. 2016 Nov 8;113(45):E7077-E7086 [PMID: 27791134]
  39. Biochim Biophys Acta Biomembr. 2018 Nov;1860(11):2404-2415 [PMID: 29902419]
  40. J Am Chem Soc. 2009 Jun 10;131(22):7609-17 [PMID: 19445503]
  41. Nat Rev Microbiol. 2020 May;18(5):275-285 [PMID: 31745331]
  42. Bio Protoc. 2017 Aug 5;7(15): [PMID: 28932762]
  43. Bio Protoc. 2018 Oct 20;8(20):e3063 [PMID: 34532528]
  44. Methods Mol Biol. 2014;1151:165-88 [PMID: 24838886]
  45. Clin Infect Dis. 2020 Jun 24;71(1):1-10 [PMID: 31404468]
  46. Proc Natl Acad Sci U S A. 2013 Sep 24;110(39):15573-8 [PMID: 24019472]

Grants

  1. R33 AI121581/NIAID NIH HHS

MeSH Term

Methicillin-Resistant Staphylococcus aureus
Microbial Sensitivity Tests
Anti-Bacterial Agents
Monobactams
Drug Resistance, Microbial

Chemicals

Anti-Bacterial Agents
Monobactams
Journal Article
Article has an altmetric score of 9

Word Cloud

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