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Insights into the Spectrum of Activity and Mechanism of Action of MGB-BP-3.
Hind, Charlotte; Clifford, Melanie; Woolley, Charlotte; Harmer, Jane; McGee, Leah M C; Tyson-Hirst, Izaak; Tait, Henry J; Brooke, Daniel P; Dancer, Stephanie J; Hunter, Iain S; Suckling, Colin J; Beveridge, Rebecca; Parkinson, John A; Sutton, J Mark; Scott, Fraser J.
Affiliation
  • Hind C; Research and Evaluation, UKHSA Porton Down, SalisburySP4 0JG, United Kingdom.
  • Clifford M; Research and Evaluation, UKHSA Porton Down, SalisburySP4 0JG, United Kingdom.
  • Woolley C; Research and Evaluation, UKHSA Porton Down, SalisburySP4 0JG, United Kingdom.
  • Harmer J; School of Applied Sciences, University of Huddersfield, Queensgate, HuddersfieldHD1 3DH, United Kingdom.
  • McGee LMC; Department of Pure and Applied Chemistry, University of Strathclyde, GlasgowG1 1XL, United Kingdom.
  • Tyson-Hirst I; Department of Pure and Applied Chemistry, University of Strathclyde, GlasgowG1 1XL, United Kingdom.
  • Tait HJ; Department of Pure and Applied Chemistry, University of Strathclyde, GlasgowG1 1XL, United Kingdom.
  • Brooke DP; Department of Pure and Applied Chemistry, University of Strathclyde, GlasgowG1 1XL, United Kingdom.
  • Dancer SJ; Department of Microbiology, Hairmyres Hospital, NHS Lanarkshire, GlasgowG75 8RG, United Kingdom.
  • Hunter IS; School of Applied Sciences, Edinburgh Napier University, EdinburghEH11 4BN, United Kingdom.
  • Suckling CJ; Strathclyde Institute of Pharmacy & Biomedical Sciences, University of Strathclyde, GlasgowG4 0RE, United Kingdom.
  • Beveridge R; Department of Pure and Applied Chemistry, University of Strathclyde, GlasgowG1 1XL, United Kingdom.
  • Parkinson JA; Department of Pure and Applied Chemistry, University of Strathclyde, GlasgowG1 1XL, United Kingdom.
  • Sutton JM; Department of Pure and Applied Chemistry, University of Strathclyde, GlasgowG1 1XL, United Kingdom.
  • Scott FJ; Research and Evaluation, UKHSA Porton Down, SalisburySP4 0JG, United Kingdom.
ACS Infect Dis ; 8(12): 2552-2563, 2022 12 09.
Article in En | MEDLINE | ID: mdl-36444998
MGB-BP-3 is a potential first-in-class antibiotic, a Strathclyde Minor Groove Binder (S-MGB), that has successfully completed Phase IIa clinical trials for the treatment of Clostridioides difficile associated disease. Its precise mechanism of action and the origin of limited activity against Gram-negative pathogens are relatively unknown. Herein, treatment with MGB-BP-3 alone significantly inhibited the bacterial growth of the Gram-positive, but not Gram-negative, bacteria as expected. Synergy assays revealed that inefficient intracellular accumulation, through both permeation and efflux, is the likely reason for lack of Gram-negative activity. MGB-BP-3 has strong interactions with its intracellular target, DNA, in both Gram-negative and Gram-positive bacteria, revealed through ultraviolet-visible (UV-vis) thermal melting and fluorescence intercalator displacement assays. MGB-BP-3 was confirmed to bind to dsDNA as a dimer using nano-electrospray ionization mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy. Type II bacterial topoisomerase inhibition assays revealed that MGB-BP-3 was able to interfere with the supercoiling action of gyrase and the relaxation and decatenation actions of topoisomerase IV of both Staphylococcus aureus and Escherichia coli. However, no evidence of stabilization of the cleavage complexes was observed, such as for fluoroquinolones, confirmed by a lack of induction of DSBs and the SOS response in E. coli reporter strains. These results highlight additional mechanisms of action of MGB-BP-3, including interference of the action of type II bacterial topoisomerases. While MGB-BP-3's lack of Gram-negative activity was confirmed, and an understanding of this presented, the recognition that MGB-BP-3 can target DNA of Gram-negative organisms will enable further iterations of design to achieve a Gram-negative active S-MGB.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Escherichia coli Language: En Journal: ACS Infect Dis Year: 2022 Document type: Article Affiliation country: United kingdom Country of publication: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Escherichia coli Language: En Journal: ACS Infect Dis Year: 2022 Document type: Article Affiliation country: United kingdom Country of publication: United States