Glucose Directly Promotes Antifungal Resistance in the Fungal Pathogen, Candida spp.

Abstract

Background: Glucose level alters susceptibility of antifungal agents during chemotherapy in diabetes patients. Results: Glucose selectively interacts with antifungal agents, strongly affects azole drugs, and forms complexes by hydrogen bonding. Conclusion: It is important for researchers and pharmaceuticals to make new antibiograms for diabetes patients. Significance: Drug selection is important for controlling fungal infections in diabetes patients.Effects of glucose on the susceptibility of antifungal agents were investigated against Candida spp. Increasing the concentration of glucose decreased the activity of antifungal agents; voriconazole was the most affected drugs followed by amphotericin B. No significant change has been observed for anidulafungin. Biophysical interactions between antifungal agents with glucose molecules were investigated using isothermal titration calorimetry, Fourier transform infrared, and 1 H NMR. Glucose has a higher affinity to bind with voriconazole by hydrogen bonding and decrease the susceptibility of antifungal agents during chemotherapy. In addition to confirming the results observed in vitro, theoretical docking studies demonstrated that voriconazole presented three important hydrogen bonds and amphotericin B presented two hydrogen bonds that stabilized the glucose. In vivo results also suggest that the physiologically relevant higher glucose level in the bloodstream of diabetes mellitus mice might interact with the available selective agents during antifungal therapy, thus decreasing glucose activity by complex formation. Thus, proper selection of drugs for diabetes mellitus patients is important to control infectious diseases. Among several emerging diseases, DM3 is considered one of the largest emerging threats to public health in the 21st century. From the medical profession to the general public, individuals are well aware that the greater frequency of metabolic disorders and morbimortality in diabetic patients are due to the hyperglycemia. Extra glucose in blood and urine provides an increased propensity to develop infections, and diabetes patients are especially prone to foot infections, yeast infections, urinary tract infections, and surgical site infections (1, 2). The prevalence of yeast infection is more common in patients with DM because of the higher density of candidal growth (3,4). Candida species are the part of the body's normal oral and intestinal flora, but infection becomes more severe in DM patients with higher levels of inflammation (5, 6). Antifungal medications, such as clotrimazole, nystatin, fluconazole, and ketoconazole, are very effective in controlling topical yeast infections. In the case of candidal infections in blood, the choices of drugs are intravenous fluconazole or echinocandin or amphotericin B (AmpB) (7,8). However, there is no such specific indication of the choice of drug for people suffering from DM. When a patient is suffering from DM and has a yeast infection, that patient is more likely to get other infections because the combinat...

Candida Survival Strategies

“…Different carbon sources substantially affect C. albicans adhesion and biofilm formation (Critchley & Douglas, 1985;Jin, Samaranayake, Samaranayake, & Yip, 2004;Samaranayake & MacFarlane, 1982). Also, the adaptation to different carbon sources influences cell wall architecture and functionality, and subsequently influences stress responses and antifungal resistance (Brown, Haynes, et al, 2012;Ene, Adya, et al, 2012;Ene, Heilmann, et al, 2012;Mandal et al, 2014). The generation of molecules such as the osmolyte glycerol, antioxidants e.g., glutathione, and the stress protectant trehalose by metabolic pathways may furthermore contribute to the regulation of stress resistance .…”

Etiologic Agents and Antifungal Susceptibility of Oral Candidosis from Romanian patients with HIV-infection or type 1 diabetes mellitus

“…This situation requires further research, especially considering the findings of a recent study that echinocandins would be a safer choice for diabetes patients since they do not seem to be affected by glucose, which appears to significantly lower the antifungal activity of azoles and polyenes (Mandal et al, 2014).…”

Glucose, Cyc8p and Tup1p regulate biofilm formation and dispersal in wild Saccharomyces cerevisiae

“…1 An increase in glucose level has been detected in blood and other body niches such as urine, intestinal fluid, mucus, sweat/perspiration and saliva 31 and is a known risk-increasing factor in fungal infections for two main reasons: Increased glucose benefits yeast cell growth and decreases the effect of some antifungal drugs. 30,32 Here we speculate about a third glucoserelated risk-increase of glucose in some niches could lead to release of adherent cells and their dispersal within the organism, potentially followed by development of new biofilms as new outbreaks of infection. We show that Cyc8p is a key factor in this process and, together with Cyc8p and Tup1p mediated antiregulation, is effective in both adherent and planktonic cells and mostly independent of growth phase.…”