Novel and potent antimicrobial effects of caspofungin on drug-resistant Candida and bacteria

Makoto Sumiyoshi,Koichi Izumikawa,Shintaro Shimamura,Koichi Makimura,Katsunori Yanagihara,Shigeru Kohno,Kazuko Yamamoto,Noriho Sakamoto,Yasushi Obase,Takahiro Takazono,Hiroyuki Yamaguchi,Takeshi Ishikawa,Juliann Nzembi Makau,Yoshimasa Tanaka,Yoshifumi Imamura,Tatsuro Hirayama,Satoshi Mizuta,Taiga Miyazaki,Tomomi Saijo,Hiroshi Mukae

doi:10.1038/s41598-020-74749-8

Makoto Sumiyoshi, Koichi Izumikawa + Show 18 more

Open Access

https://doi.org/10.1038/s41598-020-74749-8

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Abstract

Echinocandins, including caspofungin, micafungin, and anidulafungin, are first-line antifungal agents for the treatment of invasive candidiasis. They exhibit fungicidal activity by inhibiting the synthesis of β-1,3-d-glucan, an essential component of the fungal cell wall. However, they are active only against proliferating fungal cells and unable to completely eradicate fungal cells even after a 24 h drug exposure in standard time-kill assays. Surprisingly, we found that caspofungin, when dissolved in low ionic solutions, had rapid and potent antimicrobial activities against multidrug-resistant (MDR) Candida and bacteria cells even in non-growth conditions. This effect was not observed in 0.9% NaCl or other ion-containing solutions and was not exerted by other echinocandins. Furthermore, caspofungin dissolved in low ionic solutions drastically reduced mature biofilm cells of MDR Candida auris in only 5 min, as well as Candida-bacterial polymicrobial biofilms in a catheter-lock therapy model. Caspofungin displayed ion concentration-dependent conformational changes and intracellular accumulation with increased reactive oxygen species production, indicating a novel mechanism of action in low ionic conditions. Importantly, caspofungin dissolved in 5% glucose water did not exhibit increased toxicity to human cells. This study facilitates the development of new therapeutic strategies in the management of catheter-related biofilm infections.

Highlights

Echinocandins, including caspofungin, micafungin, and anidulafungin, are first-line antifungal agents for the treatment of invasive candidiasis
During our preliminary study exploring echinocandin-resistant mechanisms in C. glabrata under various environmental conditions, we found that caspofungin had potent antimicrobial activities under low ionic conditions, against Candida spp., and against drug-resistant bacteria such as methicillin-resistant Staphylococcus aureus and multidrug-resistant Pseudomonas aeruginosa
Paradoxical effect was observed with caspofungin and micafungin above the drug concentrations of 0.125 mg/L and 0.06 mg/L, respectively, at 24 h of drug exposure against C. albicans biofilm cells (Supplementary Fig. S1)

Summary

Introduction

Echinocandins, including caspofungin, micafungin, and anidulafungin, are first-line antifungal agents for the treatment of invasive candidiasis They exhibit fungicidal activity by inhibiting the synthesis of β-1,3-d-glucan, an essential component of the fungal cell wall. We found that caspofungin, when dissolved in low ionic solutions, had rapid and potent antimicrobial activities against multidrug-resistant (MDR) Candida and bacteria cells even in non-growth conditions This effect was not observed in 0.9% NaCl or other ion-containing solutions and was not exerted by other echinocandins. Echinocandins, including caspofungin, micafungin, and anidulafungin, have been widely used as first-line antifungal agents for the treatment of invasive candidiasis These compounds inhibit β-1,3-d-glucan synthesis by targeting FKS gene products and exhibit fungicidal activity against Candida spp. in vitro[3,4]. We investigated the detailed conditions regulating this unique antimicrobial capability of caspofungin and its underlying mechanisms in pathogenic organisms

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