**3.1 Discovery and development of new antifungal drugs**

This part of the chapter provides an overview of ongoing efforts to develop new classes of antifungal drugs (**Table 1**). Although there are several strategies for the development of these drugs, these include those obtained from new chemical agents, from reusing existing drugs, from peptides with antimicrobial properties, and finally from natural compounds extracted from plants [10, 55, 58].

Several new chemical-antifungals are designed specifically to target either 1,3-β-d-glucan (such as Rezafungin and Ibrexafungerp) or ergosterol (such as the compound VT-1161). These compounds are very specific for fungal infections or they have a longer half-life, offering better efficacy [58, 60–62]. At the same time, several of these antifungal agents have new targets and subsequently, new mechanisms of action. For instance, fosmanogepix, formerly APX001, and aureobasidin A, which act by inhibiting inositol acyltransferase, and inositol phosphorylceramide synthase, respectively [63, 64]. Efungumab (or Mycograb) and geldanamycin-like agents can inhibit the HSP90 chaperone, which has been also shown to confer resistance to antifungals [65, 66]. The AR-12 compound deregulates chaperone's activity by blocking fungal acetyl-CoA synthase [67]. The T-2307 compound is an arylamidine that inhibits the respiratory chain complex and is active against yeast and filamentous fungi [68]. Finally, the VL-2397 compound has a similar structure to the ferrichrome siderophore, and whose mechanism of action or its target is unknown, but it is known to be transported by the Sit1 protein [69]. Some compounds that have been already tested for other types of diseases are now receiving a new focus as antifungals. These include two compounds that enhance the antifungal activity, such as rifampin, which acts on RNA polymerase [70], and verapamil, which acts on a calcium channel [71]. We have also given importance to alternative compounds such as peptides and plant extracts; many molecules are actually studied with promising results, especially against *C. albicans*. Some peptides such as lysozyme, lactoferrin, defensins, Histatin-5, and cathelicidins are known to have antifungal properties. The main mechanism of action is due to the enhancement of substances traffic through the fungal membrane, which favours permeabilization [10, 72–76]. Plant extracts are another prominent source of new antifungals, they can act either alone or synergistically with existing antifungals to improve their function. The compounds extracted from plants are essential oils, terpenes, and flavonoids among many others. They have diverse mechanisms of action, such as alteration of the plasma membrane, binding to ergosterol, induction of apoptosis, inhibition of growth, filamentation, and biofilm formation in *C. albicans* [10, 77–81].

### **3.2 New targets and alternative approaches**

Despite the efforts made to discover, repositioning, or create new antifungal drugs, it is imperative to find new targets to help eliminating *Candida* spp. infection. The new antifungal targets include biosynthetic and signal transduction pathways, which are key players for fungal survival processes. The sphingolipids biosynthesis is a biosynthetic pathway considered as a promising target. Sphingolipids are a part of cell membranes, that act as signalling molecules regulating processes such as apoptosis. As fungal sphingolipids are structurally different to mammalian sphingolipids, they are excellent candidates for antifungal design [82]. The heat-shock proteins (Hsps) represent another potential antifungal target as they control several basic physiological activities, and heat-shock protein disruption in *C. albicans* inhibits growth or reverses tolerance to antifungals [83]. A recently studied pathway as a potential target is the ionic homeostasis signalling pathway, which is central to the fungus survival by regulating gene expression,



*Molecular Mechanisms of Resistance to Antifungals in* Candida albicans *DOI: http://dx.doi.org/10.5772/intechopen.96346*

#### **Table 1.**

*Antifungal compounds in development against* C. albicans *or* Candida *spp.*

morphological transition, response to stress, and resistance to antifungals [84]. The Ras-cAMP-PKA signal transduction pathway is essential for cellular metabolism and controls morphogenesis, adhesion, and biofilm formation, making the inactivation of this signalling cascade attractive as a target for new antifungals [85].

Finally, an alternative approach to conventional antifungal drugs is the use of nanotechnology, which produces the so-called "nanoantibiotics". These nanoantibiotics are unique due to their improved physicochemical properties, such as reduced toxicity and biocompatibility as well as their size that must be less than 100 nm [86]. The antimicrobial properties of silver have been known for a long time, so silver nanoparticles were tested as antimicrobials and showed potent activity against drug-resistant fungal biofilms [87].

#### **4. Conclusions**

A better understanding of the resistance mechanisms of azoles, polyenes, and echinocandins, along with the discovery of new cellular and clinical factors promoting resistance, will facilitate the design of more effective strategies to overcome and prevent resistance to antifungal agents. Even though several biomedical research offer a window hoping to reduce the incidence of *C. albicans* and the complications those systemic infections by this fungus entail; the quest for new targets with novel mechanisms of action continues to be the priority.

#### **Acknowledgements**

ALMR thanks the National Council of Science and Technology of Mexico (CONACyT) for the postdoctoral fellowship granted. RIAS and KCP are thankful for the scholarship granted by the National Council of Science and Technology of Mexico (CONACyT).

### **Conflict of interest**

All authors declare no conflicting interests.

*Advances in* Candida albicans
