Session: Inhibitors of Bacterial and Fungal Efflux Pumps
Location:
Exhibit Hall
Session Date:
Monday, 9/27/99
Session Time:
3:00 pm - 4:30 pm
Inhibitors of Efflux Pumps in Pseudomonas aeruginosa Potentiate the Activity of
the Fluoroquinolone Antibacterial Levofloxacin
T.E. Renau1, R. Leger1, E.M. Flamme1, J. Sangalang1, M.W. She1, R. Yen1,
C.L. Ford1, K.M. Mathias1, S. Chamberland1, S.J. Hecker1, V.J. Lee1, T.
Ohta2, K. Nakayama2
1Microcide Pharmaceuticals, Inc.: Mountain View, CA; 2Daiichi Pharmaceutical
Co. Ltd.: Tokyo, Japan
P. aeruginosa is an opportunistic pathogen characterized by intrinsic resistance to a wide
variety of antimicrobial agents, a property that has been attributed in part to the activity of
several efflux systems. We embarked on a program to identify broad-spectrum efflux
pump inhibitors in P. aeruginosa in order to potentiate the activity of the fluoroquinolone
antibacterial agent levofloxacin. To identify potential inhibitors, we screened against
specifically engineered strains of P. aeruginosa that over-expressed each of the known
pumps. Follow-up studies were implemented to confirm that the inhibitors were indeed
blocking the efflux pumps. One of the compounds identified from this effort was
MC-207,110, a low molecular weight dipeptide amide. The compound had minimal
intrinsic antibacterial activity (MIC = 256 µg/mL) but potentiated the activity of
levofloxacin 8-fold at 10 µg/mL. The overall in vitro biological profile and structural
simplicity of MC-207,110 led to its choice as the lead compound in our program. We
began an extensive medicinal chemistry effort to optimize the biological and
physicochemical properties of this lead. Herein we describe a portion of our work in this
area and disclose the first known class of broad-spectrum efflux pump inhibitors in
P. aeruginosa. |
