Effect of 1-(1-naphthylmethyl)-piperazine, a novel putative efflux pump inhibitor, on antimicrobial drug susceptibility in clinical isolates of Escherichia coli.
OBJECTIVE
1-(1-Naphthylmethyl)-piperazine (NMP) has been shown to reverse multidrug resistance (MDR) in Escherichia coli overexpressing resistance-nodulation-cell division type efflux pumps, but there is no data on its activity in clinical isolates of E. coli.


METHODS
The antimicrobial susceptibility of 60 clinical isolates of E. coli to a variety of antimicrobial agents was determined in the absence and presence of NMP and, for comparison, of Phe-Arg-beta-naphthylamide (PAbetaN), another putative efflux pump inhibitor (EPI). The intracellular accumulation of ethidium bromide was measured to confirm efflux pump inhibition as the likely mechanism of action of NMP.


RESULTS
Based on a 4-fold or greater reduction of the MIC after the addition of NMP in >50% of the isolates, significant effects of NMP at a concentration of 100 mg/L were seen for levofloxacin, linezolid and ethidium bromide. The ethidium bromide MIC changes after NMP addition correlated with differences in the ethidium bromide intracellular accumulation as measured by fluorometry in whole cell accumulation experiments. The activity of PAbetaN was different from that of NMP, in particular regarding macrolide resistance reversal, suggesting different modes of action of the two putative EPIs.


CONCLUSIONS
NMP is moderately active in reversing MDR in clinical isolates of E. coli and can partially restore fluoroquinolone susceptibility through inhibition of efflux pumps.
Kern
Winfried V
WV
Center for Infectious Diseases and Travel Medicine, Department of Medicine, University Hospital, Freiburg, Germany. kern@if-freiburg.de
Steinke
Petra
P
Schumacher
Anja
A
Schuster
Sabine
S
von Baum
Heike
H
Bohnert
Jürgen A
JA
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D003470:Culture Media; D004151:Dipeptides / Q000494:pharmacology; D024901:Drug Resistance, Multiple, Bacterial; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects* / Q000378:metabolism; D004927:Escherichia coli Infections / Q000382:microbiology; D004996:Ethidium / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D026901:Membrane Transport Proteins / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D010879:Piperazines / Q000494:pharmacology*
C409484:1-(2-naphthylmethyl)-4-benzylpiperazine; D000900:Anti-Bacterial Agents; D003470:Culture Media; D004151:Dipeptides; D004791:Enzyme Inhibitors; D008024:Ligands; D026901:Membrane Transport Proteins; D010879:Piperazines; C419365:phenylalanine arginine beta-naphthylamide; D004996:Ethidium