Fungal Infections as an Uprising Threat to Human Health: Chemosensitization of Fungal Pathogens With AFP From Aspergillus giganteus

Abstract

Occurrence and intensity of systemic invasive fungal infections have significantly risen in recent decades with large amount of mortality and morbidity rates at global level. Treatment therapy lies on the current antifungal interventions and are often limited due to the emergence of resistance to antifungal agents. Chemosensitization of fungal strains to the conventional antimycotic drugs are of growing concern. Current antifungal drugs often have been reported with poor activity and side effects to the host and have a few number of targets to manifest their efficacy on the pathogens. Indiscriminately, the aforementioned issues have been easily resolved by the development of new intervention strategies. One such approach is to employ combinational therapy that has exhibited a great level of inhibitions than that of a single compound. Chemosensitization of pathogenic mycoses to commercial antifungal drugs could be drastically enhanced by co-application of chemosensitizers along with the conventional drugs. Chemosensitizers could address the resistance mechanisms evolved in the pathogenic fungi and targeting the system to make the organism susceptible to commercially and clinically proven antifungal drugs. However, this strategy has not been overreached to the greater level, but it needs much attention to fight against not only with the pathogen but combat the resistance mechanisms of pathogens to drugs. Natural compounds including plant compounds and microbial proteins act as potential chemosensitizers to break the resistance in mycoses. Aspergillus giganteus, a filamentous fungus, is known to produce a cysteine rich extracellular protein called as antifungal protein (AFP). AFP has shown enhanced efficacy against several filamentous and non-filamentous fungal pathogens. On the basis of the reported studies on its targeted potential against pathogenic mycoses, AFP would be fabricated as a good chemosensitizer to augment the fungicidal efficacy of commercial antimycotic drugs. This paper reviews on breakthrough in the discovery of antifungal drugs along with the resistance patterns of mycoses to commercial drugs followed by the current intervention strategies applied to augment the fungicidal potential of drugs.

Keywords: AFP; Aspergillus giganteus; antifungal drugs; augmentation; chemosensitization; fungicidal activity; natural compounds.

Figure 1

Development of antimycotic drugs.

Figure 2

Schematic representation of fungal cell wall, antimycortic drugs, possible antifungal activity (target site), and resistance to commercial antifungal drugs. The picture explains various antifungal compounds and their target site on the pathogenic fungi. Along with that, the plausible resistance mechanisms evolved by the fungal species to clinically approved antimycotic drugs have clearly depicted. Resistance gene/proteins/channels might be antifungal targets for the development of novel antimycotic compounds or alternative chemosensitization/drug repurposing approaches.

Figure 3

Emergence of antifungal resistance through various mechanisms. (A) Alteration in the drug transporters reduce the accumulation of drug molecules in the cell and expel the drugs out of the cell via efflux protein transporter; two kind of major efflux pump transporters are ABC (ATP-binding cassette) protein transporters and MFS (major facilitator superfamily) protein transporters; (B) alteration in the drug targets substantially reduces the affinity of the drug for its targets by structural modification, mutation, upregulation, downregulation, and overexpression of drug targets; (C) utilization of compensatory pathways, ergosterol biosynthesis pathway alteration, and plasma membrane composition variation; (D) presence of complex multicellular structures, formation of biofilm, and polymicrobial biofilms (bacterial species often associated with one or more fungal strains).

Figure 4

Antagonistic mechanism of AFP from Aspergillus giganteus on plant and human fungal pathogens. As a biocontrol agent, it selectively inhibits and kills the growth of plant fungal pathogens by secreting specific cell-wall degrading enzymes namely, amylase, protease, β-1,3 glucanase, chitinase, and cellulase. As antifungal compounds in clinical area, it could possibly perturb the membrane of human fungal pathogens by interfering with the cell wall components and nuclear components. AFP from Aspergillus giganteus might be a promising biocontrol agent for sustainable agriculture and optimistic novel compounds for the treatment of systemic fungal infections. In addition to their remarkable values, it could be a potent chemosensitizer to sensitize the plant and human fungal pathogens to commercial fungicides and antimycotic drugs.

Figure 5

The versatile mode of action of AFP of Aspergillus giganteus.