The high rates of morbidity and mortality caused by fungal infections are associated with the current limited antifungal arsenal and the high toxicity of the compounds. Additionally, identifying novel drug targets is challenging because there are many similarities between fungal and human cells. The most common antifungal targets include fungal RNA synthesis and cell wall and membrane components, though new antifungal targets are being investigated. Nonetheless, fungi have developed resistance mechanisms, such as overexpression of eﬄux pump proteins and biofilm formation, emphasizing the importance of understanding these mechanisms. To address these problems, different approaches to preventing and treating fungal diseases are described in this review, with a focus on the resistance mechanisms of fungi, with the goal of developing efficient strategies to overcoming and preventing resistance as well as new advances in antifungal therapy. Due to the limited antifungal arsenal, researchers have sought to improve treatment via different approaches, and the synergistic effect obtained by the combination of antifungals contributes to reducing toxicity and could be an alternative for treatment. Another important issue is the development of new formulations for antifungal agents, and interest in nanoparticles as new types of carriers of antifungal drugs has increased. In addition, modifications to the chemical structures of traditional antifungals have improved their activity and pharmacokinetic parameters. Moreover, a different approach to preventing and treating fungal diseases is immunotherapy, which involves different mechanisms, such as vaccines, activation of the immune response and inducing the production of host antimicrobial molecules. Finally, the use of a mini-host has been encouraging for in vivo testing because these animal models demonstrate a good correlation with the mammalian model; they also increase the speediness of as well as facilitate the preliminary testing of new antifungal agents. In general, many years are required from discovery of a new antifungal to clinical use. However, the development of new antifungal strategies will reduce the therapeutic time and/or increase the quality of life of patients.

/pdf/antifungal-therapy-new-advances-in-the-understanding-and-2nk9zo7suk.pdf

Antifungal Therapy: New Advances in the Understanding and Treatment of Mycosis.

Candida commonly adheres to implanted medical devices, growing as a resilient biofilm capable of withstanding extraordinarily high antifungal concentrations. As currently available antifungals have minimal activity against biofilms, new drugs to treat these recalcitrant infections are urgently needed. Recent investigations have begun to shed light on the mechanisms behind the profound resistance associated with the biofilm mode of growth. This resistance appears to be multifactorial, involving both mechanisms similar to conventional, planktonic antifungal resistance, such as increased efflux pump activity, as well as mechanisms specific to the biofilm lifestyle. A unique biofilm property is the production of an extracellular matrix. Two components of this material, β-glucan and extracellular DNA, promote biofilm resistance to multiple antifungals. Biofilm formation also engages several stress response pathways that impair the activity of azole drugs. Resistance within a biofilm is often heterogeneous, with the development of a subpopulation of resistant persister cells. In this article we review the molecular mechanisms underlying Candida biofilm antifungal resistance and their relative contributions during various growth phases.

Mechanisms of Candida biofilm drug resistance

Like other microorganisms, free-living Candida albicans is mainly present in a three-dimensional multicellular structure, which is called a biofilm, rather than in a planktonic form. Candida albicans biofilms can be isolated from both abiotic and biotic surfaces at various locations within the host. As the number of abiotic implants, mainly bloodstream and urinary catheters, has been increasing, the number of biofilm-associated bloodstream or urogenital tract infections is also strongly increasing resulting in a raise in mortality. Cells within a biofilm structure show a reduced susceptibility to specific commonly used antifungals and, in addition, it has recently been shown that such cells are less sensitive to killing by components of our immune system. In this review, we summarize the most important insights in the mechanisms underlying biofilm-associated antifungal drug resistance and immune evasion strategies, focusing on the most recent advances in this area of research.

/pdf/recent-insights-into-candida-albicans-biofilm-resistance-4b4omjxumt.pdf

Recent insights into Candida albicans biofilm resistance mechanisms

There are currently few antifungals in use which show efficacy against fungal diseases. These antifungals mostly target specific components of fungal plasma membrane or its biosynthetic pathways. However, more recent class of antifungals in use is echinocandins which target the fungal cell wall components. The availability of mostly fungistatic antifungals in clinical use, often led to the development of tolerance to these very drugs by the pathogenic fungal species. Thus, the development of clinical multidrug resistance (MDR) leads to higher tolerance to drugs and its emergence is helped by multiple mechanisms. MDR is indeed a multifactorial phenomenon wherein a resistant organism possesses several mechanisms which contribute to display reduced susceptibility to not only single drug in use but also show collateral resistance to several drugs. Considering the limited availability of antifungals in use and the emergence of MDR in fungal infections, there is a continuous need for the development of novel broad spectrum antifungal drugs with better efficacy. Here, we briefly present an overview of the current understanding of the antifungal drugs in use, their mechanism of action and the emerging possible novel antifungal drugs with great promise.

Antifungals: Mechanism of Action and Drug Resistance

Candida albicans, one of the pathogenic Candida species, causes high mortality rate in immunocompromised and high-risk surgical patients. In the last decade, only one new class of antifungal drug echinocandin was applied. The increased therapy failures, such as the one caused by multi-drug resistance, demand innovative strategies for new effective antifungal drugs. Synergistic combinations of antifungals and anti-virulence agents highlight the pragmatic strategy to reduce the development of drug resistant and potentially repurpose known antifungals, which bypass the costly and time-consuming pipeline of new drug development. Anti-virulence and synergistic combination provide new options for antifungal drug discovery by counteracting the difficulty or failure of traditional therapy for fungal infections.

https://www.tandfonline.com/doi/pdf/10.1080/21505594.2015.1039885

Synergistic combinations of antifungals and anti-virulence agents to fight against Candida albicans

Combination therapy can be used for the treatment of fungal infections, especially for those caused by antifungal-resistant fungi. In the present study, in vitro interactions and mechanisms between fluconazole and minocycline against Candida albicans were evaluated. The nature of the interactions determined by spectrophotometric method in a checkerboard assay was interpreted using nonparametric models of fractional inhibitory concentration index (FICI) and percentages of growth difference (ΔE). In the mechanism study, we evaluated the potential activity of minocycline on fluconazole penetrating the C. albicans biofilm. Furthermore, the effect of fluconazole and minocycline alone and in combination on the cellular calcium balance, as well as on the uptake and efflux of fluconazole were evaluated. It was found that fluconazole can work synergistically with minocycline against fluconazole-resistant C. albicans; the minimum inhibitory concentration of fluconazole decreased from 512 to 2 microgmL(-1) when fluconazole and minocycline were given in combination, with an FICI of 0.035 and 0.064 and high-percentage synergistic interactions of 1250% and 988% for the two resistant strains. The mechanism of action was suggested to be the enhancement of minocycline on fluconazole penetrating biofilm, and inducing the intracellular calcium release, instead of impacting on the uptake and efflux of fluconazole. Our results suggest that the combination of fluconazole and minocycline can reduce the fluconazole resistance of C. albicans in vitro.

The combination of minocycline and fluconazole causes synergistic growth inhibition against Candida albicans: an in vitro interaction of antifungal and antibacterial agents.

Candida albicans is a clinically important fungus and is capable of forming biofilms, which contributes to the emergence of fluconazole resistance. Here, sessile minimum inhibitory concentrations (SMICs) of fluconazole combined with doxycycline against biofilms of C. albicans were determined, and the results of SMICs were compared with minimum inhibitory concentrations (MICs) of planktonic cells. SMICs and MICs were determined by microdilution checkerboard method, and the interactions between two drugs were interpreted by two models of fractional inhibitory concentration index and the percentage of growth difference (ΔE). For the biofilms formed over 4, 8, and 12 h, synergism was displayed by the combination of doxycycline(1-64 mg L(-1)) and fluconazole, and the fluconazole SMIC reduced from 64-512 mg L(-1) to 1-16 mg L(-1) against all the tested isolates. Calcium homeostasis is an important factor in growth of C. albicans. In this study, the impact of calcium channel blocker on the drug combination was observed by plate streaking and determined by liquid methods quantitatively. Obvious enhancement of antifungal effect appeared by combination of three drugs. These results show us that fluconazole combined with doxycycline could be effective against C. albicans biofilm, and the combined antifungal mechanism is associated with calcium.

Synergistic effect of doxycycline and fluconazole against Candida albicans biofilms and the impact of calcium channel blockers

The incidence of invasive fungal infections has increased in immunocompromised patients, with Candida albicans being the most common pathogen. Since the diagnosis of candidemia is important for the initiation of appropriate antifungal therapy, so far many diagnostic techniques, such as culture, phenotypic tests, serological tests and so on, have been developed. However, all of these methods have significant flaws that limit their usefulness in clinical practice. In this paper, we review several newly developed and modified molecular assays that have shown promise in the clinical diagnosis of Candida albicans.

Development of molecular assays in the diagnosis of Candida albicans infections

Background/purpose It is difficult to manage coinfections in critically ill patients, especially in the presence of mixed-species biofilms. The aim of this study was to seek an effective drug combination for managing the dual-species biofilm of Candida albicans and Staphylococcus aureus. Methods The interaction between fluconazole and minocycline against polymicrobial planktonic cells and polymicrobial biofilms formed over four different time intervals (4 hours, 8 hours, 12 hours, and 24 hours) was investigated using a microdilution checkerboard method. To explore whether the combined effects against the polymicrobial cultures involved calcium regulation, the effects of benidipine and ethylene glycol tetraacetic acid were characterized using a plate streaking method and a liquid-based quantitative method. Results Fluconazole combined with minocycline exerted strong effects against polymicrobial planktonic cells and polymicrobial biofilms formed over 4 hours, 8 hours, and 12 hours. The addition of benidipine and ethylene glycol tetraacetic acid enhanced the activity of the drug combination, suggesting that the combined effects may involve the perturbation of calcium homeostasis. Conclusion Fluconazole in combination with minocycline is a potential approach for counteracting C. albicans–S. aureus dual-species biofilms.

In vitro interactions between fluconazole and minocycline against mixed cultures of Candida albicans and Staphylococcus aureus

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The combination of minocycline and fluconazole causes synergistic growth inhibition against Candida albicans: an in vitro interaction of antifungal and antibacterial agents.

Synergistic effect of doxycycline and fluconazole against Candida albicans biofilms and the impact of calcium channel blockers

Development of molecular assays in the diagnosis of Candida albicans infections

In vitro interactions between fluconazole and minocycline against mixed cultures of Candida albicans and Staphylococcus aureus