Mechanisms Of Antifungal Resistance Research Articles

Resistance Mechanisms of Plant Pathogenic Fungi to Fungicide, Environmental Impacts of Fungicides, and Sustainable Solutions

The significant reduction in agricultural output and the decline in product quality are two of the most glaring negative impacts caused by plant pathogenic fungi (PPF). Furthermore, contaminated food or transit might introduce mycotoxins produced by PPF directly into the food chain. Eating food tainted with mycotoxin is extremely dangerous for both human and animal health. Using fungicides is the first choice to control PPF or their toxins in food. Fungicide resistance and its effects on the environment and public health are becoming more and more of a concern, despite the fact that chemical fungicides are used to limit PPF toxicity and control growth in crops. Fungicides induce target site alteration and efflux pump activation, and mutations in PPF result in resistance. As a result, global trends are shifting away from chemically manufactured pesticides and toward managing fungal plant diseases using various biocontrol techniques, tactics, and approaches. However, surveillance programs to monitor fungicide resistance and their environmental impact are much fewer compared to bacterial antibiotic resistance surveillance programs. In this review, we discuss the PPF that contributes to disease development in plants, the fungicides used against them, factors causing the spread of PPF and the emergence of new strains, the antifungal resistance mechanisms of PPF, health, the environmental impacts of fungicides, and the use of biocontrol agents (BCAs), antimicrobial peptides (AMPs), and nanotechnologies to control PPF as a safe and eco-friendly alternative to fungicides.

Antifungal Resistance in Candida Species: A Bit from the Totality

Abstract: Resistance to antifungals is one of the natural protection processes developed by fungi to promote their persistence. Exposure of fungi to these agents over long periods due to improper prescription or a contaminated environment increases the resistance problem. Microbiology related to fungal species and clinical settings related to the therapeutic failure of antifungal drugs are two concepts used to define resistance. The minimum inhibitory concentration (MIC) measurement is the common criterion for determining antifungal resistance. Candida spp. is the most common group of fungi that has developed resistance to different antifungal agents. C. albicans has shown resistance to numerous antifungal agents from this genus, followed by non-albicans Candida (NAC). The majority of resistance is to the azole group of antifungal agents through various mechanisms. Resistance to echinocandins is also reported in many species of Candida, while resistance to polyene has been observed in rare cases. The mechanism of resistance action is generally related to a genetic mutation, which changes the mechanisms of diffusion, fungal structure, and drug degradation. Biofilm formation also contributes to antifungal resistance. Current information on the nature and mechanism of antifungal resistance in Candida spp. is briefly presented in this review.

Phenotypic and Genotypic Characterization of Candida parapsilosis complex isolates from a Lebanese Hospital.

The opportunistic fungal pathogen Candida parapsilosis is a major causative agent of candidiasis leading to death in immunocompromised individuals. Azoles are the first line of defense in treatment by inhibiting ERG11, involved in the synthesis of ergosterol, the main sterol fungal sterol. Resistance to azoles is on the increase worldwide including in Lebanon. The purpose of this study is to characterize nine hospital isolates labeled as C. parapsilosis: four resistant and five sensitive to fluconazole. Phenotypic characterization was achieved through a battery of tests that target pathogenicity attributes such as virulence, biofilm formation, stress resistance, and ergosterol content. Genotypic analysis was done through whole genome sequencing to mutations in key virulence and resistance genes. Phylogenetic comparison was performed to determine strain relatedness and clonality. Genomic data and phylogenetic analysis revealed that three of the nine C. parapsilosis isolates were misidentified; two as C. orthopsilosis and C. metapsilosis belonging to the C. parapsilosis complex, while the third was C. albicans. Moreover, several known and novel mutations in key drug resistance and virulence genes were identified such as ERG11, ERG3, ERG6, CDR1, and FAS2. Phylogenetic analysis revealed a high degree of relatedness and clonality within our C. parapsilosis isolates. Our results showed that resistant isolates had no increased ergosterol content, no statistically significant difference in virulence, but exhibited an increase in biofilm content compared to the sensitive isolates. In conclusion, our study, the first of its kind in Lebanon, suggests several mechanisms of antifungal drug resistance in C. parapsilosis hospital isolates.

Novel antifungals and treatment approaches to tackle resistance and improve outcomes of invasive fungal disease.

SUMMARYFungal infections are on the rise, driven by a growing population at risk and climate change. Currently available antifungals include only five classes, and their utility and efficacy in antifungal treatment are limited by one or more of innate or acquired resistance in some fungi, poor penetration into "sequestered" sites, and agent-specific side effect which require frequent patient reassessment and monitoring. Agents with novel mechanisms, favorable pharmacokinetic (PK) profiles including good oral bioavailability, and fungicidal mechanism(s) are urgently needed. Here, we provide a comprehensive review of novel antifungal agents, with both improved known mechanisms of actions and new antifungal classes, currently in clinical development for treating invasive yeast, mold (filamentous fungi), Pneumocystis jirovecii infections, and dimorphic fungi (endemic mycoses). We further focus on inhaled antifungals and the role of immunotherapy in tackling fungal infections, and the specific PK/pharmacodynamic profiles, tissue distributions as well as drug-drug interactions of novel antifungals. Finally, we review antifungal resistance mechanisms, the role of use of antifungal pesticides in agriculture as drivers of drug resistance, and detail detection methods for antifungal resistance.

In vitro inhibitory activity of Riparins against Candida spp. strains and in silico interaction with multi-drug-resistance proteins

Candida spp. includes opportunistic pathogens that are responsible for superficial and invasive infections. These strains have mechanisms of resistance against antimicrobials. Riparin compounds isolated from the green fruit of the plant Aniba riparia (Nees) Mez, are alkaloids with alkamide function with notable antimicrobial properties. We evaluated the inhibitory effect (in vitro) of Riparins isolated and combined with Fluconazole against strains of Candida albicans, C. tropicalis, and C. krusei; and in an in silico test, the anti-Candida activity of the factors MdR1, CdR1, and CdR2. Riparins were identified by 1D NMR spectroscopy (1 H and 13 C), electrospray ionization mass spectrometry (ESI-MS), and compared with previously reported spectral data. For the antifungal activity profile, the broth microdilution technique was used (1–1024 µg/mL). For combined antifungal activity, Riparins were tested at fixed subinhibitory concentrations (RI, RII, and RIV of 256 µg/mL and RIII, 64 µg/mL), and FCZ, ranging from 1 to 1024 µg/mL. Minimum Fungicide Concentration was performed by microculture in Petri dishes. For molecular docking, protein sequences were obtained from GenBank; targets were analyzed for homology, and model reliability was assessed using the Ramachandran plot. Composite stratification was performed by the MolDock Score, Rerank Score, PLANTS Score, and Vina Score. The results demonstrated that Riparins I, II, III, and IV, isolated or combined with FCZ have an inhibitory effect on Candida spp. cells, and a high probability of inhibiting antifungal resistance mechanisms, MdR1, CdR1, and CdR2.

Molecular mechanisms that govern infection and antifungal resistance in Mucorales.

SUMMARYThe World Health Organization has established a fungal priority pathogens list that includes species critical or highly important to human health. Among them is the order Mucorales, a fungal group comprising at least 39 species responsible for the life-threatening infection known as mucormycosis. Despite the continuous rise in cases and the poor prognosis due to innate resistance to most antifungal drugs used in the clinic, Mucorales has received limited attention, partly because of the difficulties in performing genetic manipulations. The COVID-19 pandemic has further escalated cases, with some patients experiencing the COVID-19-associated mucormycosis, highlighting the urgent need to increase knowledge about these fungi. This review addresses significant challenges in treating the disease, including delayed and poor diagnosis, the lack of accurate global incidence estimation, and the limited treatment options. Furthermore, it focuses on the most recent discoveries regarding the mechanisms and genes involved in the development of the disease, antifungal resistance, and the host defense response. Substantial advancements have been made in identifying key fungal genes responsible for invasion and tissue damage, host receptors exploited by the fungus to invade tissues, and mechanisms of antifungal resistance. This knowledge is expected to pave the way for the development of new antifungals to combat mucormycosis. In addition, we anticipate significant progress in characterizing Mucorales biology, particularly the mechanisms involved in pathogenesis and antifungal resistance, with the possibilities offered by CRISPR-Cas9 technology for genetic manipulation of the previously intractable Mucorales species.

Mechanisms of antifungal resistance and developments in alternative strategies to combat Candida albicans infection.

Candida albicans is a commensal fungus that infects the humans and becomes an opportunistic pathogen particularly in immuno-compromised patients. Among the Candida genus, yeast C. albicans is the most frequently incriminated species and is responsible for nearly 50-90% of human candidiasis, with vulvovaginal candidiasis alone, affecting about 75% of the women worldwide. One of the significant virulence traits in C. albicans is its tendency to alternate between the yeast and hyphae morphotypes, accounting for the development of multi-drug resistance in them. Thus, a thorough comprehension of the decision points and genes controlling this transition is necessary, to understand the pathogenicity of this, naturally occurring, pernicious fungus. Additionally, the formation of C. albicans biofilm is yet another pathogenesis trait and a paramount cause of invasive candidiasis. Since 1980 and in 90s, wide spread use of immune-suppressing therapies and over prescription of fluconazole, a drug used to treat chronic fungal infections, triggered the emergence of novel anti-fungal drug development. Thus, this review thoroughly elucidates the diseases associated with C. albicans infection as well as the anti-fungal resistance mechanism associated with them and identifies the emerging therapeutic agents, along with a rigorous discussion regarding the future strategies that can possibly be adopted for the cure of this deleterious pathogen.

Population genomic analyses reveal high diversity, recombination and nosocomial transmission among Candida glabrata (Nakaseomyces glabrata) isolates causing invasive infections.

Candida glabrata is a commensal yeast of the gastrointestinal tract and skin of humans. However, it causes opportunistic infections in immunocompromised patients, and is the second most common Candida pathogen causing bloodstream infections. Although there are many studies on the epidemiology of C. glabrata infections, the fine- and large-scale geographical nature of C. glabrata remain incompletely understood. Here we investigated both the fine- and large-scale population structure of C. glabrata through genome sequencing of 80 clinical isolates obtained from six tertiary hospitals in Qatar and by comparing with global collections. Our fine-scale analyses revealed high genetic diversity within the Qatari population of C. glabrata and identified signatures of recombination, inbreeding and clonal expansion within and between hospitals, including evidence for nosocomial transmission among coronavirus disease 2019 (COVID-19) patients. In addition to signatures of recombination at the population level, both MATa and MATα alleles were detected in most hospitals, indicating the potential for sexual reproduction in clinical environments. Comparisons with global samples showed that the Qatari C. glabrata population was very similar to those from other parts of the world, consistent with the significant role of recent anthropogenic activities in shaping its population structure. Genome-wide association studies identified both known and novel genomic variants associated with reduced susceptibilities to fluconazole, 5-flucytosine and echinocandins. Together, our genomic analyses revealed the diversity, transmission patterns and antifungal drug resistance mechanisms of C. glabrata in Qatar as well as the relationships between Qatari isolates and those from other parts of the world.

Aneuploidy underlies brefeldin A-induced antifungal drug resistance in Cryptococcus neoformans.

Cryptococcus neoformans is at the top of the list of "most wanted" human pathogens. Only three classes of antifungal drugs are available for the treatment of cryptococcosis. Studies on antifungal resistance mechanisms are limited to the investigation of how a particular antifungal drug induces resistance to a particular drug, and the impact of stresses other than antifungals on the development of antifungal resistance and even cross-resistance is largely unexplored. The endoplasmic reticulum (ER) is a ubiquitous subcellular organelle of eukaryotic cells. Brefeldin A (BFA) is a widely used chemical inducer of ER stress. Here, we found that both weak and strong selection by BFA caused aneuploidy formation in C. neoformans, mainly disomy of chromosome 1, chromosome 3, and chromosome 7. Disomy of chromosome 1 conferred cross-resistance to two classes of antifungal drugs: fluconazole and 5-flucytosine, as well as hypersensitivity to amphotericin B. However, drug resistance was unstable, due to the intrinsic instability of aneuploidy. We found overexpression of AFR1 on Chr1 and GEA2 on Chr3 phenocopied BFA resistance conferred by chromosome disomy. Overexpression of AFR1 also caused resistance to fluconazole and hypersensitivity to amphotericin B. Furthermore, a strain with a deletion of AFR1 failed to form chromosome 1 disomy upon BFA treatment. Transcriptome analysis indicated that chromosome 1 disomy simultaneously upregulated AFR1, ERG11, and other efflux and ERG genes. Thus, we posit that BFA has the potential to drive the rapid development of drug resistance and even cross-resistance in C. neoformans, with genome plasticity as the accomplice.

In Vitro Susceptibility Tests in the Context of Antifungal Resistance: Beyond Minimum Inhibitory Concentration in Candida spp.

Antimicrobial resistance is a matter of rising concern, especially in fungal diseases. Multiple reports all over the world are highlighting a worrisome increase in azole- and echinocandin-resistance among fungal pathogens, especially in Candida species, as reported in the recently published fungal pathogens priority list made by WHO. Despite continuous efforts and advances in infection control, development of new antifungal molecules, and research on molecular mechanisms of antifungal resistance made by the scientific community, trends in invasive fungal diseases and associated antifungal resistance are on the rise, hindering therapeutic options and clinical cures. In this context, in vitro susceptibility testing aimed at evaluating minimum inhibitory concentrations, is still a milestone in the management of fungal diseases. However, such testing is not the only type at a microbiologist's disposal. There are other adjunctive in vitro tests aimed at evaluating fungicidal activity of antifungal molecules and also exploring tolerance to antifungals. This plethora of in vitro tests are still left behind and performed only for research purposes, but their role in the context of invasive fungal diseases associated with antifungal resistance might add resourceful information to the clinical management of patients. The aim of this review was therefore to revise and explore all other in vitro tests that could be potentially implemented in current clinical practice in resistant and difficult-to-treat cases.

Identification of Molecular and Genetic Resistance Mechanisms in a Candida auris Isolate in a Tertiary Care Center in Türkiye.

Candida auris is a multidrug-resistant pathogen that causes nosocomial outbreaks and high mortality. We conducted this study to investigate the molecular mechanisms of antifungal resistance in our clinical isolate of C. auris with a high level of resistance to three main classes of antifungals. A clinical C. auris isolate was identified by MALDI-TOF MS and antifungal susceptibilities were determined by the Sensititre YeastOne YO10 panel. After sequencing the whole genome of the microorganism with Oxford Nanopore NGS Technologies, a phylogenetic tree was drawn as a cladogram to detect where the C. auris clade to this study's assembly belongs. The C. auris isolate in this study (MaCa01) was determined to be a part of the clade I (South Asian). The resistance-related genes indicated that MaCa01 would most likely be highly resistant to fluconazole (CDR1, TAC1b, and ERG11), none or little resistant to amphotericin B (AmpB) and echinocandins, and sensitive to flucytosine. The mutations found in the above-mentioned genes in the Türkiye C. auris isolate reveals an antifungal resistance pattern. This molecular resistance pattern was found consistent with the interpretation of MIC values of the antifungals according to CDC tentative breakpoints. We detected the well-known antifungal resistance mutations, responsible for azole resistance in C. auris. Despite no ERG2, ERG6, and FKS mutation identified, the isolate was found to be resistant to AmpB and caspofungin based on the CDC tentative breakpoints which could be related to unidentified mutations.

Candida parapsilosis sensu stricto Antifungal Resistance Mechanisms and Associated Epidemiology.

Fungal diseases cause millions of deaths per year worldwide. Antifungal resistance has become a matter of great concern in public health. In recent years rates of non-albicans species have risen dramatically. Candida parapsilosis is now reported to be the second most frequent species causing candidemia in several countries in Europe, Latin America, South Africa and Asia. Rates of acquired azole resistance are reaching a worrisome threshold from multiple reports as in vitro susceptibility testing is now starting also to explore tolerance and heteroresistance to antifungal compounds. With this review, the authors seek to evaluate known antifungal resistance mechanisms and their worldwide distribution in Candida species infections with a specific focus on C. parapsilosis.

Epidemiology of Clinically Significant Aspergillus Species from a Large Tertiary Hospital in Shanghai, China, for the Period of Two Years.

Aspergillus species are becoming a major public health concern worldwide due to the increase in the incidence of aspergillosis and emergence of antifungal resistance. In this study, we surveyed all Aspergillus species isolated from aspergillosis patients in Zhongshan Hospital Fudan University, Shanghai, China, from 2019 to 2021. We characterized the susceptibility profiles of these Aspergillus species to medical azoles (voriconazole, itraconazole and posaconazole) using YeastOneTM broth microdilution system. To determine the underlying antifungal resistance mechanisms in azole-resistant A. fumigatus (ARAf) isolates, we characterized mutations in the cyp51A gene. Genotypic diversity of sampled A. fumigatus was investigated using CSP-typing. A total of 112 Aspergillus isolates (81 A. fumigatus, 17 A. flavus, 5 A. niger, 2 A. terreus, 2 A. lentulus, 2 A. oryzae, 1 A. nidulans, 1 A. versicolor and 1 A. sydowii) from 105 patients diagnosed with aspergillosis (including proven or probable invasive aspergillosis, chronic pulmonary aspergillosis, allergic bronchopulmonary aspergillosis and cutaneous aspergillosis) were obtained. Eight isolates (7 A. fumigatus and 1 A. niger) from seven patients were either azole non-susceptible or non-wild type. Azole non-susceptible or non-wild type rate was 7.1%/isolate and 6.7%/patient analysed. Four ARAf harbored TR34/L98H mutation, whereas one carried TR46/Y121F/T289A allele. The 81 A. fumigatus isolates were spread across 8 CSP types with t01 to be the predominant type (53.1%). ARAf isolates were distributed over CSP types t01, t02, t04A and t11. Results from this study provided us with an understanding of the antifungal resistance and related characteristics of Aspergillus species in Eastern China. Further comparisons of our results with those in other countries reflect potential clonal expansion of A. fumigatus in our region. Further surveillance study is warranted to guide antifungal therapy and for epidemiological purposes.

Recalcitrant cutaneous fungal infections-A growing problem.

The incidence and prevalence of recalcitrant cutaneous fungal infections is on the rise. Terbinafine-resistant Trichophyton has not only been widespread in India, but has also been reported in countries spread throughout the globe. Strains of yeasts such as Malassezia and Candida, which exist both as commensals and as pathogens to the human skin, have also been found to develop resistance to antifungals. Non-dermatophyte moulds which can colonize and infect damaged nails are especially difficult to treat, not only due to resistance, but also because of poor drug penetration of hard keratin. Psychosocial factors such as the indiscriminate broad-spectrum antifungal use in agriculture and in medicine, and poor adherence to hygienic measures to break the chain of infection contribute to the development of antifungal resistance. Such environments encourage fungi to develop various resistance mechanisms to withstand antifungal treatment. These include: (a) alteration of the drug target, (b) increasing efflux of drug/metabolites, (c) inactivation of drug, (d) bypass mechanisms or substitution of the pathway affected by the drug, (e) stress adaptation mechanisms and (f) biofilm formation. Understanding of such mechanisms and how they arise are crucial for development of new ways to prevent or overcome resistance. Novel antifungal treatments have recently been approved in the United States of America for treatment of vulvovaginal candidiasis. Ibrexafungerp (enfumafungin derivative) and oteseconazole (tetrazole) differ from their respective related drug classes of echinocandins and triazoles by having different structures, which lend these medicines advantage compared to traditional treatment by having a different binding site and more selectivity for fungi respectively. Other drugs designed to circumvent the known mechanisms of antifungal resistance are also at various phases of development. Concurrent measures at an institutional and individual level to address and limit inappropriate antifungal use to reduce development of antifungal resistance should be undertaken in a concerted effort to address this epidemic.

Fungal Drug Response and Antimicrobial Resistance

Antifungal resistance is a growing concern as it poses a significant threat to public health. Fungal infections are a significant cause of morbidity and mortality, especially in immunocompromised individuals. The limited number of antifungal agents and the emergence of resistance have led to a critical need to understand the mechanisms of antifungal drug resistance. This review provides an overview of the importance of antifungal resistance, the classes of antifungal agents, and their mode of action. It highlights the molecular mechanisms of antifungal drug resistance, including alterations in drug modification, activation, and availability. In addition, the review discusses the response to drugs via the regulation of multidrug efflux systems and antifungal drug-target interactions. We emphasize the importance of understanding the molecular mechanisms of antifungal drug resistance to develop effective strategies to combat the emergence of resistance and highlight the need for continued research to identify new targets for antifungal drug development and explore alternative therapeutic options to overcome resistance. Overall, an understanding of antifungal drug resistance and its mechanisms will be indispensable for the field of antifungal drug development and clinical management of fungal infections.

Candida parapsilosis Virulence and Antifungal Resistance Mechanisms: A Comprehensive Review of Key Determinants.

Candida parapsilosis is the second most common Candida species isolated in Asia, Southern Europe, and Latin America and is often involved in invasive infections that seriously impact human health. This pathogen is part of the psilosis complex, which also includes Candida orthopsilosis and Candida metapsilosis. C. parapsilosis infections are particularly prevalent among neonates with low birth weights, individuals who are immunocompromised, and patients who require prolonged use of a central venous catheter or other indwelling devices, whose surfaces C. parapsilosis exhibits an enhanced capacity to adhere to and form biofilms. Despite this well-acknowledged prevalence, the biology of C. parapsilosis has not been as extensively explored as that of Candida albicans. In this paper, we describe the molecular mechanistic pathways of virulence in C. parapsilosis and show how they differ from those of C. albicans. We also describe the mode of action of antifungal drugs used for the treatment of Candida infections, namely, polyenes, echinocandins, and azoles, as well as the resistance mechanisms developed by C. parapsilosis to overcome them. Finally, we stress the importance of the ongoing search for species-specific features that may aid the development of effective control strategies and thus reduce the burden on patients and healthcare costs.

Recent developments in membrane targeting antifungal agents to mitigate antifungal resistance.

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.

Antifungal susceptibility profiles and drug resistance mechanisms of clinical Candida duobushaemulonii isolates from China.

Candida duobushaemulonii, type II Candida haemulonii complex, is closely related to Candida auris and capable of causing invasive and non-invasive infections in humans. Eleven strains of C. duobushaemulonii were collected from China Hospital Invasive Fungal Surveillance Net (CHIF-NET) and identified using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF), VITEK 2 Yeast Identification Card (YST), and internal transcribed spacer (ITS) sequencing. Whole genome sequencing of C. duobushaemulonii was done to determine their genotypes. Furthermore, C. duobushaemulonii strains were tested by Sensititre YeastOne™ and Clinical and Laboratory Institute (CLSI) broth microdilution panel for antifungal susceptibility. Three C. duobushaemulonii could not be identified by VITEK 2. All 11 isolates had high minimum inhibitory concentrations (MICs) to amphotericin B more than 2 μg/ml. One isolate showed a high MIC value of ≥64 μg/ml to 5-flucytosine. All isolates were wild type (WT) for triazoles and echinocandins. FUR1 variation may result in C. duobushaemulonii with high MIC to 5-flucytosine. Candida duobushaemulonii mainly infects patients with weakened immunity, and the amphotericin B resistance of these isolates might represent a challenge to clinical treatment.

Molecular Mechanisms of Antifungal Resistance in Mucormycosis.

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.

Voriconazole Treatment Induces a Conserved Sterol/Pleiotropic Drug Resistance Regulatory Network, including an Alternative Ergosterol Biosynthesis Pathway, in the Clinically Important FSSC Species, Fusarium keratoplasticum.

Fusarium keratoplasticum is the Fusarium species most commonly associated with human infections (fusariosis). Antifungal treatment of fusariosis is often hampered by limited treatment options due to resistance towards azole antifungals. The mechanisms of antifungal resistance and sterol biosynthesis in fusaria are poorly understood. Therefore, in this study we assessed the transcriptional response of F. keratoplasticum when exposed to voriconazole. Our results revealed a group of dramatically upregulated ergosterol biosynthesis gene duplicates, most notably erg6A (912-fold), cyp51A (52-fold) and ebp1 (20-fold), which are likely part of an alternative ergosterol biosynthesis salvage pathway. The presence of human cholesterol biosynthesis gene homologs in F. keratoplasticum (ebp1, dhcr7 and dhcr24_1, dhcr24_2 and dhcr24_3) suggests that additional sterol biosynthesis pathways may be induced in fusaria under other growth conditions or during host invasion. Voriconazole also induced the expression of a number of ABC efflux pumps. Further investigations suggested that the highly conserved master regulator of ergosterol biosynthesis, FkSR, and the pleiotropic drug resistance network that induces zinc-cluster transcription factor FkAtrR coordinate the response of FSSC species to azole antifungal exposure. In-depth genome mining also helped clarify the ergosterol biosynthesis pathways of moulds and provided a better understanding of antifungal drug resistance mechanisms in fusaria.