Promising antifungal activity of new oxadiazole against Candida krusei

Abstract

Candida krusei is one of the most common agents of invasive candidiasis and candidemia worldwide, leading to high morbidity and mortality rates. This species has become a problem due to its intrinsic resistance and reduced susceptibility to azoles and polyenes. Moreover, the number of antifungal drugs available for candidiasis treatment is limited, demonstrating the urgent need for the discovery of novel alternative therapies. In this work, the in vivo and in vitro activities of a new oxadiazole (LMM11) were evaluated against C. krusei. The minimum inhibitory concentration ranged from 32 to 64 μg/mL with a significant reduction in the colony forming unit (CFU) count (~3 log 10). LMM11 showed fungicidal effect, similar to amphotericin, reducing the viable cell number (>99.9%) in the time-kill curve. Yeast cells presented morphological alterations and inactive metabolism when treated with LMM11. This compound was also effective in decreasing C. krusei replication inside and outside macrophages. A synergistic effect between fluconazole and LMM11 was observed. In vivo treatment with the new oxadiazole led to a significant reduction in CFU (0.85 log 10). Furthermore, histopathological analysis of the treated group exhibited a reduction in the inflammatory area. Taken together, these results indicate that LMM11 is a promising candidate for the development of a new antifungal agent for the treatment of infections caused by resistant Candida species such as C. krusei.

Fungicidal Activity of a Safe 1,3,4-Oxadiazole Derivative Against Candida albicans

“…In this study, we demonstrated a more promising effect of LMM6, as compared to others 1,3,4-oxadiazoles previously tested in our laboratory [ 21 , 22 , 23 ]. The LMM6 antifungal activity in vitro clearly reveals reduction in the number of C. albicans viable cells (CFU quantitative analysis) in which it was confirmed by growth decrease by CFM.…”

“…Additionally, it is absent in humans, that can contribute with the development of selective drugs against pathogens [ 25 ]. 1,3,4-oxadiazole-based drugs have been widely studied by researchers [ 21 , 22 , 23 , 26 , 27 , 28 , 29 ]. These compounds have a high therapeutic power and broad spectrum of action, such as anticancer, antifungal, antibacterial, antitubercular, anti-inflammatory, antineuropathic, antihypertensive, antihistaminic, antiparasitic, antiobesity, antiviral activity, among others [ 29 ].…”

“…These compounds have shown promise against important pathogenic fungi, such as Candida spp., Cryptococcus neoformans and Paracoccidioides spp. with low toxicity in vitro and in vivo [ 20 , 21 , 22 , 23 ]. In this study, we evaluated the antifungal activity against C. albicans as well as the toxicity in murine model of LMM6 compound, which also belongs to the oxadiazole class and it was selected by in silico approach based on similarity to the LMM11 [ 20 ].…”

One Century of Study: What We Learned about Paracoccidioides and How This Pathogen Contributed to Advances in Antifungal Therapy

“…Research using the thioredoxin system as a target for treatment for fungal infections has increased in recent years [ 97 , 114 , 126 , 127 , 128 , 129 , 130 , 131 ]. The identification of essential genes is a strategy that elucidates new targets for antifungal therapy, and when widely conserved in fungi, there is an increased interest in acting as new targets for drug design [ 97 ].…”

“…The inhibitory activity in vitro was 64.9 μM, without cellular toxicity and, most importantly, significantly reduced the fungal burden on the kidneys of mice in the candidemia experimental model [ 128 ]. One of these oxadiazole compounds, named LMM11, showed activity against C. krusei with MICs ranging from 65 to 129.9 μM, and it also succeeded in reducing colony-forming unit (CFU) recovered from the kidneys of infected mice with this clinically-relevant pathogen, mostly involved in hospital infections [ 130 ]. The two oxadiazoles (LMM5 and LMM11) selected against TRR1 showed a range of inhibitory action from 2.03 to 71.99 μM against nine isolates of Paracoccidioides spp.…”