Journal
COMMUNICATIONS BIOLOGY
Volume 6, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s42003-023-04412-1
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Type IA topoisomerases maintain DNA topology by cleaving ssDNA and relaxing negative supercoils. Inhibition of bacterial TopoIA activity by PPEF and BPVF inhibits DNA metabolic processes and leads to cell death. PPEF specifically stabilizes the topoisomerase and its complex with ssDNA, acting as an interfacial inhibitor.
Type IA topoisomerases maintain DNA topology by cleaving ssDNA and relaxing negative supercoils. The inhibition of its activity in bacteria prevents the relaxation of negative supercoils, which in turn impedes DNA metabolic processes leading to cell death. Using this hypothesis, two bisbenzimidazoles, PPEF and BPVF are synthesized, selectively inhibiting bacterial TopoIA and TopoIII. PPEF stabilizes the topoisomerase and topoisomerase-ssDNA complex, acts as an interfacial inhibitor. PPEF display high efficacy against similar to 455 multi-drug resistant gram positive and negative bacteria. To understand molecular mechanism of inhibition of TopoIA and PPEF, accelerated MD simulation is carried out, and results suggested that PPEF binds, stabilizes the closed conformation of TopoIA with -6Kcal/mol binding energy and destabilizes the binding of ssDNA. The TopoIA gate dynamics model can be used as a tool to screen TopoIA inhibitors as therapeutic candidates. PPEF and BPVF cause cellular filamentation and DNA fragmentation leading to bacterial cell death. PPEF and BPVF show potent efficacy against systemic and neutropenic mouse models harboring E. coli, VRSA, and MRSA infection without cellular toxicity.
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