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
Impact of MC-510,027, a Fungal Efflux Pump Inhibitor, on the Susceptibility of Clinical Isolates of
Candida spp. to Antifungal Agents
S. Chamberland, J. Blais, D.P. Cotter, M.K. Hoang, J. Galazzo, A. Staley, M. Lee, G.H. Miller
Microcide Pharmaceuticals, Inc.: Mountain View, CA
Resistance to azoles is often mediated by overexpression or modification of their primary target (14-alpha
demethylase) or overexpression of efflux pumps capable of reducing the intracellular concentration of drug.
We have identified a natural product (MC 510027) that acts as a fungal efflux pump inhibitor (FEPI).
Combinations of MC-510,027 and itraconazole (Itra), fluconazole (Flu), terbinafine (Terb) or Sch 56592
(Sch) were tested against 139 recent clinical isolates of 9 species of Candida. MICs were determined using a
broth microdilution assay in RPMI. MC-510,027 is devoid of significant antifungal activity. The effect of
MC-510,027 on the susceptibility of clinical isolates to antifungal agents is summarized below:
Yeast (n)
MIC90 (µg/ml) to drug alone or with MC-510,027 (+)
Itra
Itra +
SCh
SCh +
Flu
Flu +
Terb
Terb+
C. albicans (92)
>8
0.03
>8
0.002
>128
8
>32
4
C. glabrata (19)
>8
1
8
1
128
16
>32
16
C. tropicalis (11)
>8
0.008
>8
0.002
>128
1
>32
4
Candida spp.* (17)
4
0.125
4
0.06
>128
16
>32
>32
* Candida spp. include: 8 C. krusei, 3 C. parapsilosis, 2 C. guillermondii, 2 C. pseudotropicalis, 1 C.
lipolytica and 1 C. stellatoidea.
MC-510,027 enhanced the activity of azoles in all species of Candida tested, even though their relative
intrinsic susceptibility varied over a wide range. These data indicate that drug efflux plays an important role in
both intrinsic and acquired resistance to azoles and terbinafine in recent clinical isolates of Candida. Inhibition
of fungal efflux pumps may lead to a significant increase in susceptibility to currently used antifungal agents. |
