Molecular Mechanisms of Antifungal Resistance in Mucormycosis

Abstract

Mucormycosis is one among the life-threatening fungal infections with high morbidity and mortality. It is an uncommon and rare infection targeting people with altered immunity. This lethal infection induced by fungi belonging to the Mucorales family is very progressive in nature. The incidence has increased in recent decades owing to the rise in immunocompromised patients. Disease management involves a multimodal strategy including early administration of drugs and surgical removal of infected tissues. Among the antifungals, azoles and amphotericin B remain the gold standard drugs of choice for initial treatment. The order Mucorales are developing a high level of resistance to the available systemic antifungal drugs, and the efficacy still remains below par. Deciphering the molecular mechanisms behind the antifungal resistance in Mucormycosis would add vital information to our available antifungal armamentarium and design novel therapies. Therefore, in this review, we have discussed the mechanisms behind Mucormycosis antifungal resistance. Moreover, this review also highlights the basic mechanisms of action of antifungal drugs and the resistance landscape which is expected to augment future treatment strategies.

Comprehensive Review on the Virulence Factors and Therapeutic Strategies with the Aid of Artificial Intelligence against Mucormycosis

“…190 Although both nystatin and amphotericin B are polyenes, the latter is effective solely in systemic therapy against mucormycosis. 152 Though effective, AmB use requires close monitoring due to nephrotoxicity risk. 191,192 Its severe side effects include loss of essential ions, leading to nephrotoxicity and anaphylaxis.…”

“…152 Azoles further boost ROS generation, like polyenes, hindering fungal growth. 152 Posaconazole (a hydroxylated analogue of itraconazole) and Isavuconazole are used as second-line therapies for mucormycosis. Though novel, they demonstrate greater efficacy against Mucorales in vitro compared to other triazoles, voriconazole, itraconazole, and fluconazole.…”

“…Amphotericin B (AmB, a polyene), commonly used for mucormycosis (at high doses of 5–10 mg/kg/day), sequesters ergosterol in fungal membranes, making fungal membranes porous and ROS generation, causing cell disruption and death . Although both nystatin and amphotericin B are polyenes, the latter is effective solely in systemic therapy against mucormycosis . Though effective, AmB use requires close monitoring due to nephrotoxicity risk. , Its severe side effects include loss of essential ions, leading to nephrotoxicity and anaphylaxis .…”

“…Triazoles (five-member azole ring with two (imidazole) or three (triazole) nitrogen atoms connected to a side chain), used as a second-line treatment, often considered for severe cases, inhibit 14-demethylation, leading to the accumulation of toxic 14-methyl sterol and altering fungal membrane permeability. ,, Ergosterol, the primary sterol in fungal membranes and nonessential for humans, is synthesized by about 25 enzymes, among which, lanosterol 14-demethylase (Erg11p) is a key target for antifungal drug discovery . It is inhibited by azoles, reducing ergosterol levels and creating toxic sterols through subsequent enzymes (Erg6p, Erg25p, Erg26p, Erg27p, and Erg3p) . Azoles further boost ROS generation, like polyenes, hindering fungal growth .…”

“…150−152 A thorough investigation of this pathway for combating drug resistance involving next-generation sequencing and functional genomics is crucial to uncover key virulence factors. 152 Dicer-dependent RNAi pathway drives antifungal drug resistance in Mucorales, facilitated by proteins like RNA-dependent RNA polymerases (RdRPs) (paralogues, rdrp-1, rdrp-2 have been identified in M. circinelloides), 153,154 RNase III endonuclease (Dicer/Dcl1, Dcl2), and the RNA-induced silencing complex (RISC) carrying argonaute proteins for cleaving target mRNA. 68,153,155,156 Additionally, two proteins, the quelling-induced protein (QIP) and helicase (RnhA), activate this epigenetic process alongside basic RNAi proteins.…”