Abstract:
The synergistic anticandidal activity of three
diketopiperazines [cyclo-(L-Pro-L-Leu) (1), cyclo-(D-Pro-
L-Leu) (2), and cyclo-(D-Pro-L-Tyr) (3)] purified from a
Bacillus sp. N strain associated with entomopathogenic
nematode Rhabditis (Oscheius) in combination with
amphotericin B and clotrimazole was investigated using
the macrodilution method. The minimum inhibitory concentration
and minimum fungicidal concentration of the
diketopiperazines was compared with that of the standard
antibiotics. The synergistic anticandidal activities of
diketopiperazines with amphotericin B or clotrimazole were
assessed using the checkerboard and time-kill methods. The
results of the present study showed that the combined effects
of diketopiperazines with amphotericin B or clotrimazole
predominantly recorded synergistic (<0.5). Time-kill study
showed that the growth of the Candida was completely
attenuated after 12–24 h of treatment with 50:50 ratios of
diketopiperazines and antibiotics. These results suggest that
diketopiperazines combined with antibiotics may be
microbiologically beneficial and not antagonistic. These
findings have potential implications in delaying the development
of resistance as the anticandidal effect is achieved
with lower concentrations of both drugs (diketopiperazines
and antibiotics). The cytotoxicity of diketopiperazines was
also tested against two normal human cell lines (L231 lung
epithelial and FS normal fibroblast) and no cytotoxicity was
recorded for diketopiperazines up to 200 μg/mL. The in vitro
synergistic activity of diketopiperazines with antibiotics
against Candida albicans is reported here for the first time.
