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

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.

The Fungicidal Action of Micafungin is Independent on Both Oxidative Stress Generation and HOG Pathway Signaling in Candida albicans

“…Here, we demonstrate that MF acts in a different way; our experimental evidence with MF strongly supports that this antifungal does not induce ROS formation or increase antioxidant enzyme activities or gene expressions ( Figure 2 , Figure 4 and Figure 5 ) [ 27 ], albeit MF exhibits fungicidal activity against C. albicans . Supporting these data, CAS was the only echinocandin able to induce mitochondrion-derived ROS in the filamentous fungus Aspergillus fumigatus [ 47 ] and to undergo conformational changes in low ionic solution with a subsequent increase of its toxicity, attributed to a higher ROS production, in multidrug resistance Candida and bacteria cells [ 48 ]. In order to fortify our conclusions, we made use of mutants defective in the MAPK Hog1, which are hypersensitive to oxidants [ 23 ].…”

Potential of Polyethyleneimine as an Adjuvant To Prepare Long-Term and Potent Antifungal Nanovaccine

“…C. albicans is one of the most common reasons of Candida infections, also causing high mortality and morbidity in immunocompromised patients ( 38 ). A mortality of 40% has been reported in patients with invasive candidiasis, even with the proper treatment with current antifungal drugs ( 39 ). Antifungal vaccine is the primary method of prevention, especially for those with weakened immune systems.…”

Candida auris: A Quick Review on Identification, Current Treatments, and Challenges

“…Authors reported interference of aprepitant/itraconazole with metal ion homeostasis, which led to losing reactive oxygen species' detoxification ability [114]. [115,116] Biofilms formed by Candida spp. on indwelling catheters are difficult to treat.…”

“…This strategy was selected in the work of Sumiyoshi and colleagues. Caspofungin was dissolved in low ionic solutions and a considerable reduction of candidal (including resistant C. auris) was noticed in the polymicrobial biofilms present in the catheter-lock therapy model [116].…”