Insights into the Spectrum of Activity and Mechanism of Action of MGB-BP-3

• DOI: 10.1021/acsinfecdis.2c00445
• Publication Date: 2022-11-29T13:04:30Z
• Authors: Charlotte Hind; Melanie Clifford; Charlotte Woolley; Jane Harmer; Leah M. C. McGee; Izaak Tyson-Hirst; Henry J. Tait; Daniel P. Brooke; Stephanie J. Dancer; Iain S. Hunter; Colin J. Suckling; Rebecca Beveridge; John A. Parkinson; J. Mark Sutton; Fraser J. Scott
• Keywords: Mechanism of Action

MGB-BP-3 is a potential first-in-class antibiotic, 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 action and origin limited activity against Gram-negative pathogens are relatively unknown. Herein, with alone significantly inhibited bacterial growth Gram-positive, but not Gram-negative, bacteria as expected. Synergy assays revealed inefficient intracellular accumulation, through both permeation efflux, likely reason lack activity. strong interactions its target, DNA, in Gram-positive bacteria, ultraviolet–visible (UV–vis) thermal melting fluorescence intercalator displacement assays. was confirmed to bind dsDNA dimer using nano-electrospray ionization mass spectrometry nuclear magnetic resonance (NMR) spectroscopy. Type II topoisomerase inhibition able interfere supercoiling gyrase relaxation decatenation actions IV Staphylococcus aureus Escherichia coli. However, no evidence stabilization cleavage complexes observed, such fluoroquinolones, by induction DSBs SOS response E. coli reporter strains. These results highlight additional mechanisms MGB-BP-3, including interference type topoisomerases. While MGB-BP-3′s confirmed, an understanding this presented, recognition can target DNA organisms will enable further iterations design achieve active S-MGB.