Monoterpenes, including piperitone, increase nitrofurantoin susceptibility in members of the family Enterobacteriaceae. To understand interactions of these compounds, a nitrofurantoin-resistant clinical strain of Enterobacter cloacae was subjected to two-dimensional checkerboard dilutions of piperitone and nitrofurantoin. Synergy was demonstrated with all combinations of these compounds. HPLC analysis showed that E. cloacae metabolized nitrofurantoin to compounds that were not detectable by chromatography with UV detection and lacked bactericidal activity. E. cloacae produced a cell-associated nitroreductase, whose activity was reduced by piperitone in a dose-dependent manner. More than one mechanism may be involved in the synergistic interaction of these compounds.
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