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Published on: April 19, 2017
Predictive Nephrotoxicity Profiling of a Novel Antifungal Small Molecule in Comparison to Amphotericin B and
Nadeeka S Udawatte1, Sung Wook Kang2, Yue Wang3
1National Dental Centre Singapore, Oral Health ACP, Duke-NUS Medical School, Singapore, Singapore.
Background And Purpose:
Candida albicans is the major fungal species associated with superficial mucosal infections such as oral candidiasis as well as systemic mycoses with high morbidity and mortality. On top of the rising drug resistance, currently available antifungal agents have significant adverse effects. Nephrotoxicity is the major treatment complication associated with antifungal agents.Recently, we discovered a novel antifungal small molecule SM21 with promising antifungal activity. The present study aimed to comparatively evaluate the in vivo and in vitro nephrotoxicity of SM21 comparing with Amphotericin B and voriconazole.
Experimental Approach:
Nephrotoxicity of SM21 and its analogue were comparatively evaluated with Amphotericin B (AmB) and voriconazole. Immortalized human kidney proximal tubule epithelial cells (HK-2) were used for in vitro analysis of nephrotoxicity using cytotoxicity assays and qPCR gene expression analysis (Kim-1/HAVcr-1, CASP3). Sprague Dawley (SD) rat model was used to evaluate the nephrotoxicity in vivo using classical (SCr and BUN) and next-generation kidney injury urinary biomarkers (Kim-1, CLU, ALB, NGAL, β2M, and Cys C) alongside histopathological and immunohistochemical standards.
Key Results:
AmB treatment showed a stronger cytotoxic impact on HK-2 viability and gene expression of cell death markers (Kim-1/HAVcr-1, CASP3) compared with SM21 and SM21 analogue in vitro (P < 0.01). In vivo data further demonstrated that SM21 did not significantly increase classical as well as novel nephrotoxic biomarkers, and minimal renal tubular necrosis and abnormalities were observed (15 mg kg-1 BW/day).
Conclusions And Implications:
SM21 had a significantly better safety profile in terms of nephrotoxicity with no major tubular epithelial abnormalities observed in kidney cells and no augmentation of kidney injury biomarkers compared to AmB. Kim-1 and CLU were the most sensitive biomarkers for detection of AmB-induced kidney damage. Future clinical trials should consider inclusion of these novel biomarkers as early indicators of acute kidney injury in antifungal-induced nephrotoxicity.
Insights
A novel antifungal SM21 shows reduced nephrotoxicity compared to Amphotericin B. This new drug candidate offers a safer profile for treating fungal infections, with minimal kidney damage observed in studies.
Area of Science:
- Pharmacology
- Toxicology
- Mycology
Background:
- Candida albicans causes significant mucosal and systemic infections.
- Current antifungals face rising resistance and adverse effects, notably nephrotoxicity.
- Novel antifungal SM21 demonstrates promising activity but requires safety evaluation.
Purpose of the Study:
- To comparatively evaluate the in vitro and in vivo nephrotoxicity of SM21 against Amphotericin B and voriconazole.
- To assess the safety profile of SM21 as a potential antifungal agent.
Main Methods:
- In vitro: Cytotoxicity and gene expression (Kim-1/HAVcr-1, CASP3) in human kidney proximal tubule cells (HK-2).
- In vivo: Sprague Dawley rats assessed using classical (SCr, BUN) and novel urinary biomarkers (Kim-1, CLU, ALB, NGAL, β2M, Cys C), plus histopathology.
- Comparative analysis with Amphotericin B (AmB) and voriconazole.
Main Results:
- SM21 exhibited significantly less cytotoxicity and lower induction of cell death markers in HK-2 cells compared to AmB in vitro.
- In vivo, SM21 did not significantly elevate kidney injury biomarkers and showed minimal renal tubular damage.
- AmB demonstrated a stronger cytotoxic impact and induced higher levels of kidney damage markers.
Conclusions:
- SM21 possesses a superior safety profile regarding nephrotoxicity compared to AmB.
- No significant kidney injury biomarkers or tubular abnormalities were observed with SM21 treatment.
- Novel biomarkers Kim-1 and CLU are sensitive indicators of AmB-induced nephrotoxicity, recommended for future clinical trials.
