TY - JOUR
T1 - Novel and potent antimicrobial effects of caspofungin on drug-resistant Candida and bacteria
AU - Sumiyoshi, Makoto
AU - Miyazaki, Taiga
AU - Makau, Juliann Nzembi
AU - Mizuta, Satoshi
AU - Tanaka, Yoshimasa
AU - Ishikawa, Takeshi
AU - Makimura, Koichi
AU - Hirayama, Tatsuro
AU - Takazono, Takahiro
AU - Saijo, Tomomi
AU - Yamaguchi, Hiroyuki
AU - Shimamura, Shintaro
AU - Yamamoto, Kazuko
AU - Imamura, Yoshifumi
AU - Sakamoto, Noriho
AU - Obase, Yasushi
AU - Izumikawa, Koichi
AU - Yanagihara, Katsunori
AU - Kohno, Shigeru
AU - Mukae, Hiroshi
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85093116541&partnerID=8YFLogxK
U2 - 10.1038/s41598-020-74749-8
DO - 10.1038/s41598-020-74749-8
M3 - 記事
C2 - 33082485
AN - SCOPUS:85093116541
SN - 2045-2322
VL - 10
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 17745
ER -