Dermatophytes comprise pathogenic fungi that have a high affinity for the keratinized structures present in nails, skin, and hair, causing superficial infections known as dermatophytosis. A reasonable number of antifungal drugs currently exist on the pharmaceutical market to control mycoses; however, their cellular targets are restricted, and fungi may exhibit tolerance or resistance to these agents. For example, the stress caused by antifungal and cytotoxic drugs in sub-inhibitory concentrations promotes compensatory stress responses, with the over-expression of genes involved in cellular detoxification, drug efflux, and signaling pathways being among the various mechanisms that may contribute to drug tolerance. In addition, the ATP-binding cassette transporters in dermatophytes that are responsible for cellular efflux can act synergistically, allowing one to compensate for the absence of the other, revealing the complexity of drug tolerance phenomena. Moreover, mutations in genes coding for target enzymes could lead to substitutions in amino acids involved in the binding of antifungal agents, hindering their performance and leading to treatment failure. The relevance of each one of these mechanisms of resistance to fungal survival is hard to define, mainly because they can act simultaneously in the cell. However, an understanding of the molecular mechanisms involved in the resistance/tolerance processes, the identification of new antifungal targets, as well as the prospective of new antifungal compounds among natural or synthetic products, are expected to bring advances and new insights that facilitate the improvement or development of novel strategies for antifungal therapy.

The increasing use of antimicrobial drugs has been linked to the rise of drug-resistant fungus in recent years. Antimicrobial resistance is being studied from a variety of perspectives due to the important clinical implication of resistance. The processes underlying this resistance, enhanced methods for identifying resistance when it emerges, alternate treatment options for infections caused by resistant organisms, and so on are reviewed, along with strategies to prevent and regulate the formation and spread of resistance. This overview will focus on the action mechanism of antifungals and the resistance mechanisms against them. The link between antibacterial and antifungal resistance is also briefly discussed. Based on their mechanism action, antifungals are divided into three distinct categories: azoles, which target the ergosterol synthesis; 5-fluorocytosine, which targets macromolecular synthesis and polyenes, which interact physiochemically with fungal membrane sterols. Antifungal resistance can arise through a wide variety of ways. Overexpression of the target of the antifungal drug, changes to the drug target, changes to sterol biosynthesis, decreased intercellular concentration of the target enzyme, and other processes. A correlation exists between the mechanisms of resistance to antibacterial and antifungals, despite the fact that the comparison between the two is inevitably constrained by various parameters mentioned in the review. Drug extrusion via membrane pumps has been thoroughly documented in both prokaryotic and eukaryotic cells, and development of new antifungal compounds and strategies has also been well characterized.

Twelve drugs from four chemical classes are currently available for treatment of systemic fungal infections in humans. By contrast, more than 100 structurally distinct compounds from over 30 chemical classes have been developed as agricultural fungicides, and these fungicides target many modes of action not represented among human antifungal drugs. In this article we introduce the diverse aspects of agricultural fungicides and compare them with human antifungal drugs. We propose that the information gained from the development of agricultural fungicides can be applied to the discovery of new mechanisms of action and new antifungal agents for the management of human fungal infections.

Abstract Yeasts belonging to the Candida genus are important human pathogens. Candida biofilm is the most common resistance mechanism, which could increase in 1000 times the resistance to antifungal drugs. This study aimed to evaluate the antibiofilm activity of synthetic peptides, as well as action mechanisms and synergistic effect with Nystatin (NYS) and Itraconazole (ITR) by Scanning Electron Microscopy (SEM) and Fluorescence Microscopy (FM). ITR (1000 µg. mL− 1) inhibited 10% of biofilm formation of C. krusei and NYS (1000 µg. mL− 1) 40% of C. albicans. Regarding synergistic effect, peptides enhance 7-fold the action of ITR to inhibit the biofilm formation of C. krusei and C. albicans, as well as the degradation of formed biofilm of C. krusei. The action mechanism of peptides or in combination with antifungal drugs involved cell wall damage, membrane pore formation, loss of cytoplasmic content, and overproduction of reactive oxygen species (ROS). Docking analysis revealed ionic and hydrophobic interactions between peptides and both drugs, which may explain the synergistic effect. Altogether, our results suggest the high potential of synthetic peptides be employed as adjuvants enhancing the activity of antifungal drugs to overcome the resistance provided by fungal biofilm and decrease the toxicity of drugs.

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.

Although the arsenal of agents with anti-Aspergillus activity has expanded over the last decade, mortality due to invasive aspergillosis remains unacceptably high. Resistance of the Aspergillus spp. species to antifungal drugs increased in the last 20 years with the increase in antifungal drugs use and might partially account for treatment failures. Recent advances in our understanding of mechanisms of antifungal drug action in Aspergillus, along with the standardization of in vitro susceptibility testing methods, have brought resistance testing to the forefront of clinical mycology. Recent modifications in taxonomy and understanding of the acquired resistance mechanisms of Aspergilli to drugs should support a better management of Aspergillus infections. In this paper, we review the current knowledge on epidemiology and underlying mechanisms involved in antifungal resistance in Aspergillus.

Azole antimycotics are a well-known and important class of agents that are used in hospital practice, everyday health care, veterinary medicine and for crop protection. The era of azole fungicides began with the breakthrough of chlormidazole roughly 50 years ago. Since then, more than 20 drugs of this group, including triazoles, have been brought to the market. The specific chemical structure and mechanism of the action of azoles along with the eukaryotic character of fungal pathogens raise several serious issues. Resistance to drugs and disturbance to metabolic pathways are among the most important. On the other hand, these same features are responsible for unique and novel applications of these drugs. As a result, old and ineffective antifungal drugs can be successfully used in the treatment of parasitic diseases, bacterial infections or cancers. Are azoles getting their second wind?

Background: Dermatomycosis is a type of fungal infection that can infect human skin, hair, and nails; an increasing growth of fungal infections ranging from superficial to systemic infection is alarming. Common causative agents are Candida, Cryptococcus, Aspergillus, and Pneumocystis species. A wide range of antifungal drugs is used for the treatment of mycotic infections. These antifungal drugs can be oral or topical. The topical therapy ensures reduced side effects. Some act as fungistatic, while others act as fungicidal. These drugs work by a different mechanism of action to prevent and cure fungal infections. Objective: The effective treatment of the fungal infection includ the use of proper antifungal drug therapy. Antifungal drugs are classified into various classes. This paper focuses on understanding and interpreting the detailed molecular and cellular mechanism of action of various classes of anti-fungal drugs with their important characteristics along with the safety and efficacy data of individual drugs of the particular class. Methods: The data selection for carrying out the respective study has been made by studying the combination of review articles and research papers from different databases, like ResearchGate, PubMed, MDPI, Elsevier, ScienceDirect, and MedCrave, ranging from the year 1972 to 2019, by using the keywords like “anti-fungal agents”, “dermatophytes”, “cutaneous candidiasis”, “superficial fungal infections”, “oral candidiasis”, “amphotericin”, “echinocandins”, “azoles”, “polyenes” “ketoconazole”, “terbinafine”, “griseofulvin”, “azoles”. Result: Based on interpretation, it is concluded that the different classes of antifungal drugs follow the different mechanisms of action and target the fungal cell membrane, and are efficient in reducing fungal disease by their respective mechanism. Conclusion: The prevention and cure of fungal infections can be done by oral or topical antifungal drugs aimed to destroy the fungal cell membrane. These drugs show action by their respective pathways that are either preventing the formation of ergosterol or squalene or act by inhibiting the β-1,3- glucan synthase enzyme. All the drugs are found to be effective in treating fungal infections.

Early treatment of invasive fungal infections (IFIs) is essential for optimal clinical outcomes. Standard antifungal drugs (polyenes, azoles and echinocandins) are not predictably effective against emerging yeasts and filamentous fungi and may cause undesirable side effects. Species identification can guide antifungal selection for invasive candidiasis, but not less common moulds such as Scedosporium and Fusarium spp. Management strategies targeted to those at highest risk (prophylaxis), those with clinical signs of infection not responsive to antibacterials (empiric therapy) and those with occult infection (asymptomatic but with positive fungal biomarkers) produce better outcomes than therapy predicated on identification of a fungal pathogen, but require comparative evaluation. Appropriate dosing and consideration of pharmacokinetic parameters (including therapeutic drug monitoring) are important with newer triazoles. New therapies such as addition of the iron chelator, deferasirox, in the treatment of zygomycosis in diabetic patients, appear promising but additional agents with new targets of action are urgently needed.

Fungal infections cause severe and life-threatening complications especially in immunocompromised individuals. Antifungals targeting cellular machinery and cell membranes including azoles are used in clinical practice to manage topical to systemic fungal infections. However, continuous exposure to clinically used antifungal agents in managing the fungal infections results in the development of multi-drug resistance via adapting different kinds of intrinsic and extrinsic mechanisms. The unique chemical composition of fungal membranes presents attractive targets for antifungal drug discovery as it is difficult for fungal cells to modify the membrane targets for emergence of drug resistance. Here, we discussed available antifungal drugs with their detailed mechanism of action and described different antifungal resistance mechanisms. We further emphasized structure-activity relationship studies of membrane-targeting antifungal agents, and classified membrane-targeting antifungal agents on the basis of their core scaffold with detailed pharmacological properties. This review aims to pique the interest of potential researchers who could explore this interesting and intricate fungal realm.