Molecular Mechanisms of Action of Herbal Antifungal Alkaloid Berberine, in Candida albicans

Abstract

Candida albicans causes superficial to systemic infections in immuno-compromised individuals. The concomitant use of fungistatic drugs and the lack of cidal drugs frequently result in strains that could withstand commonly used antifungals, and display multidrug resistance (MDR). In search of novel fungicidals, in this study, we have explored a plant alkaloid berberine (BER) for its antifungal potential. For this, we screened an in-house transcription factor (TF) mutant library of C. albicans strains towards their susceptibility to BER. Our screen of TF mutant strains identified a heat shock factor (HSF1), which has a central role in thermal adaptation, to be most responsive to BER treatment. Interestingly, HSF1 mutant was not only highly susceptible to BER but also displayed collateral susceptibility towards drugs targeting cell wall (CW) and ergosterol biosynthesis. Notably, BER treatment alone could affect the CW integrity as was evident from the growth retardation of MAP kinase and calcineurin pathway null mutant strains and transmission electron microscopy. However, unlike BER, HSF1 effect on CW appeared to be independent of MAP kinase and Calcineurin pathway genes. Additionally, unlike hsf1 null strain, BER treatment of Candida cells resulted in dysfunctional mitochondria, which was evident from its slow growth in non-fermentative carbon source and poor labeling with mitochondrial membrane potential sensitive probe. This phenotype was reinforced with an enhanced ROS levels coinciding with the up-regulated oxidative stress genes in BER-treated cells. Together, our study not only describes the molecular mechanism of BER fungicidal activity but also unravels a new role of evolutionary conserved HSF1, in MDR of Candida.

Sensitization of Candida albicans to terbinafine by berberine and berberrubine

“…The cell death mechanisms of berberine against C. albicans have been fully addressed in the previous studies. They involved the ability to impair mitochondrial function, generation of reactive oxygen species, targeting cell wall integrity pathway and also affecting heat shock transcription factor, HSF1 (28). The MIC and MFC values of terbinafine against C. albicans were determined as 6 and 24 µg/ml, respectively.…”

Inhibition of respiratory syncytial virus replication and virus-induced p38 kinase activity by berberine

“…Berberine has been used as an antibacterial and antifungal agent in traditional folk herbal medicine and as a dietary supplement in Asian countries, including China. Over the past several decades, numerous biological effects of berberine have been discovered, such as its anticancer [6], antilipogenic and hypoglycemic [7], neuroprotective [8], and antimicrobial effects against fungal pathogens [9] and bacterial pathogens [10]. In addition, berberine has been shown to exert antiviral effects against viruses such as herpes simplex virus, human cytomegalovirus, and influenza A virus [11][12][13].…”

<i>In-Vitro</i> Comparison of Antifungal Activity of Herbs (Darehald and Pomegranate) with Azoles

“…It is well documented that antifungal activity of B. aristata is mainly due to its alkaloid constituent known as "Berberine" that inhibits fungal cell wall, ergosterol biosynthesis and mitochondrial functions. Interestingly it has been evaluated innocuous to human being cells [45]. According to our results shown in Table 1, the second highest mean inhibitory zone (17.48 ± 4.03 mm) against candidal strains was shown by P. granatum.…”