ml300169x_si_001.txt (272.09 kB)
Antimicrobial Activity of Adenine-Based Inhibitors of NAD+-Dependent DNA Ligase
dataset
posted on 2012-08-09, 00:00 authored by Ed T. Buurman, Valerie A. Laganas, Ce Feng Liu, John I. ManchesterThe relationship between enzyme inhibition and antimicrobial
potency
of adenine-based NAD+-dependent DNA ligase (LigA) inhibitors
was investigated using a strain of the Gram-negative pathogen Haemophilus influenzae lacking its major AcrAB-TolC efflux
pump and the Gram-positive pathogen Streptococcus pneumoniae. To this end, biochemical inhibitors not mediating their antibacterial
mode of action (MOA) via LigA were removed from the analysis. In doing
so, a significant number of compounds were identified that acted via
inhibition of LigA in S. pneumoniae but not in H. influenzae, despite being inhibitors of both isozymes.
Deviations from the line correlating antimicrobial and biochemical
potencies of LigA inhibitors with the correct MOA were observed for
both species. These deviations, usually corresponding to higher MIC/IC50 ratios, were attributed to varying compound permeance into
the cell.