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In vitro synergistic activity of diketopiperazines alone and in combination with amphotericin B or clotrimazole against Candida albicans

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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.

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Acknowledgments

The authors are grateful to Indian Council Medical Research (ICMR) and the Government of India for funding. We thank the Director, CTCRI, for providing facilities for the work.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Division of Crop Protection/Division of Crop Utilization, Central Tuber Crops Research Institute, Sreekariyam, Thiruvananthapuram, 695017, India

    S. Nishanth Kumar, Bala Nambisan & C. Mohandas

  2. Division of Crop Protection, Central Tuber Crops Research Institute, Sreekariyam, Thiruvananthapuram, 695017, India

    S. Nishanth Kumar

  3. Agroprocessing and Natural Product Division, National Institute for Interdisciplinary Science and Technology (NIIST), Thiruvananthapuram, Kerala, India

    A. Sundaresan

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  1. S. Nishanth Kumar
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Correspondence to S. Nishanth Kumar.

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Kumar, S.N., Nambisan, B., Mohandas, C. et al. In vitro synergistic activity of diketopiperazines alone and in combination with amphotericin B or clotrimazole against Candida albicans . Folia Microbiol 58, 475–482 (2013). https://doi.org/10.1007/s12223-013-0234-x

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