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

Abstract

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.

In vitro antifungal activity of amphotericin B and 11 comparators against Aspergillus terreus species complex

“…The emergence of drug resistance in fungal infections is one of the most significant epidemiological changes in current decades . Thus, therapeutic options available for the treatment of these infections have become limited . Amphotericin B is generally considered the mainstay of treatment of severe fungal infections.…”

“…1 Thus, therapeutic options available for the treatment of these infections have become limited. 2 Amphotericin B is generally considered the mainstay of treatment of severe fungal infections. Invasive fungal infections due to Aspergillus terreus are difficult to treat because of the intrinsic resistance to amphotericin B, and higher mortality compared to infections caused by other Aspergillus species.…”

Heteroresistance and fungi

“…Resistance and tolerance are terms generally used to describe a phenomenon in a whole microorganism's population . Resistance is the inherited feature of fungal to grow at high concentrations of an antifungal drug . In the other way, tolerance is more generally used to describe the ability, of microorganisms to survive transient exposure to drug stress without a change in the minimum inhibitory concentration (MIC), which is frequently attained by retardation of the cell division multiplication .…”

“…5 Resistance is the inherited feature of fungal to grow at high concentrations of an antifungal drug. 6 In the other way, tolerance is more generally used to describe the ability, of microorganisms to survive transient exposure to drug stress without a change in the minimum inhibitory concentration (MIC), which is frequently attained by retardation of the cell division multiplication. 5,7 The MIC for a tolerant population is analogous to that of a susceptible one, besides the minimum duration for killing [MDK; for example for 99% of bacterial cells in the population (MDK99)] for a tolerant strain is higher than the MDK99 for a susceptible strain.…”

Computational vaccinology approach: Designing an efficient multi-epitope peptide vaccine againstCryptococcus neoformans var. grubii’sheat shock 70KDa protein

“…Current antifungal therapies are not effective in eradicating the pathogens because of the precipitation of a significant toxicity as in life-threatening Cryptococcus-related immune reconstitution inflammatory syndrome, which is detected mostly in HIV individuals whom are on antiviral with antifungal therapy (23,32,(109)(110)(111)(112)(113)(114)(115)(116)(117). In addition, the widespread use of intravascular catheters and irrational use of broad spectrum antibiotic has led to the increasing incidence of multi-drug resistant organisms, serious opportunistic, and nosocomial infections, eventually may necessitate a prolonged therapy or experience disease relapses (32,34,62,(118)(119)(120)(121)(122). Yet, to date there is no FDA authorized vaccine available to combat cryptococcosis.…”