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

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

Fungal pathogens are a growing threat to public health. As human immunodeficiency becomes increasingly common, fungal infections are becoming more prevalent. The use of antifungal agents for prophylaxis and treatment of fungal infections has favored the emergence of previously rare or unidentified species of drug-resistant fungal pathogens, including several Candida and Cryptococcus species, as well as mold pathogens. As these new and increasingly drug-resistant fungal pathogens continue to emerge, novel strategies for rapid identification and treatment are necessary to combat these life-threatening infections.

New pathogens, new tricks: emerging, drug-resistant fungal pathogens and future prospects for antifungal therapeutics.

Review of flavonoids: A diverse group of natural compounds with anti-Candida albicans activity in vitro

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 krusei is intrinsically resistant to fluconazole (FLC). This study aimed to investigate whether tacrolimus (FK506) could enhance the susceptibility of FLC against C. krusei. The tested strains included the following: five isolates with minimal inhibitory concentration (MIC) of 32 μg mL(-1), two with MIC of 256 μg mL(-1), and one with MIC of 512 μg mL(-1). MICs of FK506 and FLC alone and in combination were determined by checkerboard assay, with data analyzed by fractional inhibitory concentration index model. The time-kill curves were plotted to investigate the antifungal activity at 0, 6, 12, 24, and 48 h after drug exposure. The results revealed that FK506 reduced the resistance of all isolates obviously and degree of reduction in MICs varied with susceptibilities of strains. Addition of FK506 resulted in a fourfold and 16-fold downward shift in MICs of the isolates with MICs of 32 μg mL(-1) and of ≥ 256 μg mL(-1), respectively. The synergy was further confirmed by the time-kill assay. When they were in combination against CK4/CK9 with MIC of 32/256 μg mL(-1), there was a 2.25/2.03 log10 CFU mL(-1) decrease at 24 h compared with FLC alone, respectively. In conclusion, combination of FK506 and FLC may represent a promising approach of overcoming the intrinsic resistance of C. krusei to FLC.

A promising approach of overcoming the intrinsic resistance of Candida krusei to fluconazole (FLC) – combining tacrolimus with FLC

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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.

A promising approach of overcoming the intrinsic resistance of Candida krusei to fluconazole (FLC) – combining tacrolimus with FLC