BACKGROUND:Fungal diseases present a significant threat to global agriculture, necessitating the development of new, safe, and effective fungicides. Existing fungicides face resistance and health risks, prompting the synthesis of novel compounds. Researchers have synthesized aldehyde-based thiourea and thiazolyl hydrazine derivatives, evaluating their antifungal activities to identify impactful pesticide molecules. RESULTS:The results showed that most of the compounds had broad-spectrum antifungal activity against six plant pathogenic fungi and four post-harvest fungi. Notably, compound LN18 showed the best antifungal activity against Monilinia fructicola with a half-maximal effective concentration (EC) of 0.17 μg mL, which was better than the commercial fungicide natamycin. A structure-activity relationship (SAR) study showed that the presence of unsaturated double bonds in the structure and the length of the carbon chain were the main factors affecting antifungal activity. The presence of unsaturated double bonds and an increase in the length of the carbon chain greatly improved inhibitory activity against the tested pathogens. The preliminary mechanism study showed that LN18 could damage the integrity of the mycelial plasma membrane, leading to leakage of intracellular nucleic acid and protein. LN18 also induced an increase in the intracellular reactive oxygen species level to exert its antifungal effects. In addition, compound LN18 had a stronger antifungal effect in vivo, and better phytotoxicity than natamycin, indicating broad application prospects in agriculture. CONCLUSION:Aldehydes-thiourea and thiazolyl hydrazine derivatives demonstrate remarkable antifungal efficacy against plant pathogenic and post-harvest fungi, offering a promising avenue for commercialization as highly efficacious, cost-effective and safe antifungal agents. © 2024 Society of Chemical Industry.

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), 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.

Worldwide, invasive candidiasis are a burden for the health system due to difficulties to manage patients, to the increasing of the resistance of the current therapeutics and the emergence of naturally resistant species of . In this context, the development of innovative antifungal drugs is urgently needed. During invasive candidiasis, yeast is submitted to many stresses (oxidative, thermic, osmotic) in the human host. In order to resist in this context, yeast develops different strategy, especially the biosynthesis of trehalose. Starting from the 3D structural data of TPS2, an enzyme implicated in trehalose biosynthesis, we identified hydrazone as an interesting scaffold to design new antifungal drugs. Interestingly, our hydrazone derivatives which demonstrate antifungal and anti-biofilm effects on ., are non-toxic in and models ().

Scientists are becoming alarmed by the rise in drug-resistant bacterial and fungal strains, which makes it more costly, time-consuming, and difficult to create new antimicrobials from unique chemical entities. Chemicals with pharmacological qualities, such as antibacterial and antifungal elements, can be found in plants. Alkaloids are a class of chemical compounds found in nature that mostly consist of basic nitrogen atoms. Biomedical science relies heavily on alkaloid compounds. Based on 241 papers published in peer-reviewed scientific publications within the last ten years (2014-2024), we examined 248 natural or synthesized monomeric alkaloids that have antifungal and antibacterial activity against Gram-positive and Gram-negative microorganisms. Based on their chemical structure, the chosen alkaloids were divided into four groups: polyamine alkaloids, alkaloids with nitrogen in the side chain, alkaloids with nitrogen heterocycles, and pseudoalkaloids. With MIC values of less than 1 µg/mL, compounds , , , -, , , , , and shown strong antibacterial activity. However, with MIC values of below 1 µg/mL, compounds , , , , , and demonstrated strong antifungal activity. Given the rise in antibiotic resistance, these alkaloids are highly significant in regard to their potential to create novel antimicrobial drugs.

Antifungal peptides (AFPs) are small cationic peptides that are found in a diverse range of taxa including bacteria, plants, mammals and insects. AFPs exhibit the strong antifungal activities against several pathogenic fungi, making them potential candidates for developing novel antifungal agents. AFP cause fungal cell death by rupturing the membranes of the fungal cell wall and inhibits the vital enzymes. Since AFPs are isolated from a range of natural sources, efforts are being made to create synthetic versions of these peptides with improved pharmacological properties. One of their key advantages is that they are less likely to develop resistance as compared to conventional antifungal medications. Although AFPs display immense potential as antifungal agents, challenges still exist in their stability, solubility, absorption, and time-consuming extraction process. Still, the possibility for AFPs to evolve into a novel class of antifungal medicine gives hope for improved treatments for fungal infections. This article offers the comprehensive information on AFPs origin, mode of action, prospective use in antifungal treatments. It also discusses about the application of antifungal peptides beyond the therapeutic field, such as in agriculture for crop protection, in food industry and in aquaculture field. It further elaborates on the challenges and potential paths associated with the progression of AFPs as advanced antifungal agents.

Drug-resistant fungal infections pose a significant threat to human health. Dual-targeting compounds, which have multiple targets on a single pathogen, offer an effective approach to combat drug-resistant pathogens, although ensuring potent activity and high selectivity remains a challenge. Here we propose a dual-targeting strategy for designing antifungal compounds. We incorporate DNA-binding naphthalene groups as the hydrophobic moieties into the host defence peptide-mimicking poly(2-oxazoline)s. This resulted in a compound, (GlyNap), which targets both the fungal membrane and DNA. This compound kills clinical strains of multidrug-resistant fungi including Candida spp., Cryptococcus neoformans, Cryptococcus gattii and Aspergillus fumigatus. (GlyNap) shows superior performance compared with amphotericin B by showing not only potent antifungal activities but also high antifungal selectivity. The compound also does not induce antimicrobial resistance. Moreover, (GlyNap) exhibits promising in vivo therapeutic activities against drug-resistant Candida albicans in mouse models of skin abrasion, corneal infection and systemic infection. This study shows that dual-targeting antifungal compounds may be effective in combating drug-resistant fungal pathogens and mitigating fungal resistance.

has emerged as a problematic fungal pathogen associated with high morbidity and mortality. Amphotericin B (AmB) is the most effective antifungal used to treat invasive fungal candidiasis, with resistance rarely observed among clinical isolates. However, possesses extraordinary resistant profiles against all available antifungal drugs, including AmB. In our pursuit of potential solutions, we screened a panel of 727 FDA-approved drugs. We identified the proton pump inhibitor lansoprazole (LNP) as a potent enhancer of AmB's activity against LNP also potentiates the antifungal activity of AmB against other medically important species of and Our investigations into the mechanism of action unveiled that LNP metabolite(s) interact with a crucial target in the mitochondrial respiratory chain (complex III, known as cytochrome ). This interaction increases oxidative stress within fungal cells. Our results demonstrated the critical role of an active respiratory function in the antifungal activity of LNP. Most importantly, LNP restored the efficacy of AmB in an immunocompromised mouse model, resulting in a 1.7-log (∼98%) CFU reduction in the burden of in the kidneys. Our findings strongly advocate for a comprehensive evaluation of LNP as a cytochrome inhibitor for combating drug-resistant infections.

causes an estimated half-billion cases of vulvovaginal candidiasis (VVC) every year. VVC is most commonly caused by , which, in this setting, triggers nonprotective neutrophil infiltration, aggressive local inflammation, and symptomatic disease. Despite its prevalence, little is known about the molecular mechanisms underpinning the immunopathology of this fungal infection. In this study, we describe the molecular determinant of VVC immunopathology and a potentially straightforward way to prevent disease. In response to zinc limitation, releases a trace mineral binding molecule called Pra1 (pH-regulated antigen). Here, we show that the gene is strongly up-regulated during vaginal infections and that its expression positively correlated with proinflammatory cytokine concentrations in women. Genetic deletion of prevented vaginal inflammation in mice, and application of a zinc solution down-regulated expression of the gene and also blocked immunopathology. We also show that treatment of women suffering from recurrent VVC with a zinc gel prevented reinfections. We have therefore identified a key mediator of symptomatic VVC, giving us an opportunity to develop a range of preventative measures for combatting this disease.

In many ways, fungal diseases are forgotten or neglected. Given the significantly lower frequency compared to similar bacterial etiologies across the spectrum of infectious syndromes, it makes sense that anti-bacterial agents have seen the bulk of development in recent decades. The vast majority of new antifungal medications approved for use in the past 10 years have been new versions in the same class as existing agents. Clinical mycology is crying out for new mechanisms of action in the setting of rising resistance and emergence of new organisms. Fortunately, this trend appears to be reversing. There are numerous agents in advanced stages of development offering novel dosing regimens and mechanisms of action to combat these threats. Herein we review seven antifungal agents that we hope to see come to market in the coming years to aid physicians in the treatment of mucocutaneous and invasive fungal infections.

Fungal infections of the central nervous system (FI-CNS) are a problematic and important medical challenge considering that those most affected are immunocompromised. Individuals with systemic cryptococcosis (67-84%), candidiasis (3-64%), blastomycosis (40%), coccidioidomycosis (25%), histoplasmosis (5-20%), mucormycosis (12%), and aspergillosis (4-6%) are highly susceptible to develop CNS involvement, which often results in high mortality (15-100%) depending on the mycosis and the affected immunosuppressed population. Current antifungal drugs are limited, prone to resistance, present host toxicity, and show reduced brain penetration, making FI-CNS very difficult to treat. Given these limitations and the rise in FI-CNS, there is a need for innovative strategies for therapeutic development and treatments to manage FI-CNS in at-risk populations. Here, we discuss standards of care, antifungal drug candidates, and novel molecular targets in the blood-brain barrier, which is a protective structure that regulates movement of particles in and out of the brain, to prevent and combat FI-CNS.

Microorganisms have a remarkable capacity to evolve resistance to antimicrobial agents, threatening the efficacy of the limited arsenal of antimicrobials and becoming a dire public health crisis. This is of particular concern for fungal pathogens, which cause devastating invasive infections with treatment options limited to only three major classes of antifungal drugs. The paucity of antifungals with clinical utility is in part due to close evolutionary relationships between these eukaryotic pathogens and their human hosts, which limits the unique targets to be exploited therapeutically. This review highlights the mechanisms by which fungal pathogens of humans evolve resistance to antifungal drugs, which provide crucial insights to enable development of novel therapeutic strategies to thwart drug resistance and combat fungal infectious disease.

Antifungal drug resistance is a critical concern, demanding innovative therapeutic solutions. The dual-targeting mechanism of action (MoA), as an effective strategy to reduce drug resistance, has been validated in the design of antibacterial agents. However, the structural similarities between mammalian and fungal cells complicate the development of such a strategy for antifungal agents as the selectivity can be compromised. Herein, we introduce a dual-targeting strategy addressing fungal infections by selectively introducing DNA binding molecules into fungal nuclei. We incorporate rigid hydrophobic units into a DNA-binding domain to fabricate antifungal luminogens of TPY and TPZ, which exhibit enhanced membrane penetration and DNA-binding capabilities. These compounds exhibit dual-targeting MoA by depolarizing fungal membranes and inducing DNA damage, amplifying their potency against fungal pathogens with undetectable drug resistance. TPY and TPZ demonstrated robust antifungal activity in vitro and exhibited ideal therapeutic efficacy in a murine model of -induced vaginitis. This multifaceted approach holds promise for overcoming drug resistance and advancing antifungal therapy.

OBJECTIVES:Fluconazole (FLC) tolerant phenotypes in Candida species contribute to persistent candidemia and the emergence of FLC resistance. Therefore, making FLC fungicidal and eliminating FLC tolerance are important for treating invasive fungal diseases (IFDs) caused by Candida species. However, the mechanisms of FLC tolerance in Candida species remain to be fully explored. METHODS:This review discusses the high incidence of FLC tolerance in Candida species and the importance of successfully clearing FLC tolerance in treating candidiasis. We further define and characterize FLC tolerance in C. albicans. RESULTS:This review identifies global factors affecting FLC tolerance and suggest that FLC tolerance is a strategy of C. albicans response to FLC damage whose mechanism differs from FLC resistance. CONCLUSIONS:This review highlights the significance of the cell membrane and cell wall integrity in FLC tolerance, guiding approaches to combat IFDs caused by Candida species..

Pathogenic fungi have emerged as significant causes of infectious morbidity and death in patients with acquired immunodeficiency conditions such as HIV/AIDS and following receipt of chemotherapy, immunosuppressive agents or targeted biologics for neoplastic or autoimmune diseases, or transplants for end organ failure. Furthermore, in recent years, the spread of multidrug-resistant Candida auris has caused life-threatening outbreaks in health-care facilities worldwide and raised serious concerns for global public health. Rapid progress in the discovery and functional characterization of inborn errors of immunity that predispose to fungal disease and the development of clinically relevant animal models have enhanced our understanding of fungal recognition and effector pathways and adaptive immune responses. In this Review, we synthesize our current understanding of the cellular and molecular determinants of mammalian antifungal immunity, focusing on observations that show promise for informing risk stratification, prognosis, prophylaxis and therapies to combat life-threatening fungal infections in vulnerable patient populations.

Antibiotics are currently used for the treatment of (), which is confirmed to be the major cause of gastric disorders. However, the long-term consumption of antibiotics has already caused antibiotic resistance and side effects in vivo. Therefore, there is an emerging need for searching for safe and effective anti- agents. Inspired by the excellent bioactivities of cinnamic acid, a series of cinnamic acid derivatives (compounds -) were synthesized and determined for inhibition. The initial screening revealed that compound , a 2,4-dinitro cinnamic acid derivative containing 4-methoxyphenol, showed excellent inhibition with an MIC value of 4 μM. Further studies indicated that compound showed anti-bacterial activity and had a bactericidal effect on due to the destruction of the bacterial structure. Molecular docking analysis revealed that the 2,4-dinitro groups in cinnamic acid moiety formed hydrogen bonding with amino acid residues in an active pocket of protein. Interestingly, the ester moiety fitted into the hydrophobic pocket, attaining additional stability to compound . Above all, the present study reveals that compound could be considered a promising anti- agent to treat causing gastritis.

During recent decades, the emergence of pathogenic fungi has posed an increasing public health threat, particularly given the limited number of antifungal drugs available to treat invasive infections. In this Review, we discuss the global emergence and spread of three emerging antifungal-resistant fungi: Candida auris, driven by global health-care transmission and possibly facilitated by climate change; azole-resistant Aspergillus fumigatus, driven by the selection facilitated by azole fungicide use in agricultural and other settings; and Trichophyton indotineae, driven by the under-regulated use of over-the-counter high-potency corticosteroid-containing antifungal creams. The diversity of the fungi themselves and the drivers of their emergence make it clear that we cannot predict what might emerge next. Therefore, vigilance is critical to monitoring fungal emergence, as well as the rise in overall antifungal resistance.

Fungal infections can lead to debilitating consequences if they are not treated effectively. Antifungal drugs used to treat these infections can be toxic and overuse contributes to growing antifungal resistance. Candida spp., particularly C. albicans, are implicated in a majority of these infections. Virulent C. albicans produce secreted aspartic proteases (Saps) that aid in pathogen tissue invasion and proliferation at an infected site. Here, fungi-responsive hydrogels are developed that degrade in the presence of Saps to provide a triggered release of encapsulated liposomal antifungals. The hydrogel backbone incorporates a Sap-cleavable peptide sequence enabling Sap-responsive degradation. Hydrogels are found to effectively degrade in the presence of Saps extracted from C. albicans. Encapsulated liposomal antifungals show similar release kinetics as hydrogel degradation products in the presence of Saps, supporting a degradation-dependent release mechanism. Antifungal liposome-loaded responsive hydrogels exhibit successful eradication of C. albicans cultures and remain stable in sterile murine wound fluid. Finally, no significant cytotoxicity is observed for murine fibroblast cells and red blood cells exposed to hydrogel degradation products. These fungi-responsive hydrogels have the potential to be used for local, on-demand delivery of antifungal drugs, for effective treatment of fungal infections while helping to limit unnecessary exposure to these therapeutics.

Thirty-six structurally diverse sesquiterpenoids, including caryolanes (1-12), germacranes (13-16), isodaucane (17), cadinanes (18-22), epicubenols (23, 24), oplopanane (25), pallenanes (26, 27), and eudesmanes (28-36), were isolated from the fermentation broth of Streptomyces fulvorobeus derived from Elephas maximus feces. Pallenane is a kind of rarely reported sesquiterpene with a distinctive C5/C3 bicyclic skeleton and was firstly found from microbial source. The structures of fifteen new compounds (1-4, 13-15, 17, 18, 22, 23, 25-28) were established through detailed spectroscopic data analysis, which included data from experimental and calculated ECD spectra as well as Mosher's reagent derivative method. Compound 34 exhibited moderate antifungal activity against Cryptococcus neoformans and Cryptococcus gattii with MIC values of 50 μg/mL. It effectively inhibited biofilm formation and destroyed the preformed biofilm, as well as hindered the adhesion of Cryptococcus species. The current work would enrich the chemical diversity of sesquiterpenoid family.

Diverse betulinic acid-dithiocarbamate conjugates were designed and synthesized a two-step reaction at room temperature. Among the fourteen dithiocarbamate analogs of betulinic acid, DTC2 demonstrated the best antifungal activity against , with a minimum inhibitory concentration (MIC) of 4 μg mL, achieving 99% fungicidal activity at the same concentration. These compounds were found to be ineffective against common Gram-negative and Gram-positive pathogens, suggesting their specificity to fungi. Furthermore, DTC2 exhibited synergistic effects with the antifungal drugs fluconazole and nystatin, resulting in a significant decrease in MIC by 64 and 16 folds, respectively, when co-administered. Notably, the molecule also hindered hyphae formation in , thereby reducing its pathogenicity. Furthermore, it displayed time- and concentration-dependent kill kinetics, sterilizing within 8 hours at 8× MIC. Additionally, DTC2 exhibits greater efficacy against β-carbonic anhydrase with better docking scores and binding patterns than ethoxyzolamide, a well-known inhibitor of β-carbonic anhydrase.

Fungal infections pose a growing public health threat, creating an urgent clinical need for new antifungals. Natural products (NPs) from organisms in extreme environments are a promising source for novel drugs. CBMAI 1855 exhibited significant potential in this regard. This study aimed to (1) assess the antifungal spectrum of the CBMAI 1855 extract against key human pathogens, (2) elicit NP production through co-cultivation with fungi, correlating the metabolites with the biosynthetic gene clusters (BGCs), and (3) perform in silico toxicity predictions of the identified compounds to analyze their suitability for drug development. The crude extract of CBMAI 1855 exhibited broad-spectrum antifungal activity. The metabolomic analysis identified antifungal NPs such as antimycin A, fungimycin, surugamides, 9-(4-aminophenyl)-3,7-dihydroxy-2,4,6-trimethyl-9-oxo-nonoic acid, and ikarugamycin, with the latter two predicted to be the most suitable for drug development. Genome mining revealed three cryptic BGCs potentially encoding novel antifungals. These BGCs warrant a detailed investigation to elucidate their metabolic products and harness their potential. CBMAI 1855 is a prolific producer of multiple antifungal agents, offering a valuable source for drug discovery. This study highlights the importance of exploring microbial interactions to uncover therapeutics against fungal infections, with a detailed exploration of cryptic BGCs offering a pathway to novel antifungal compounds.

has emerged as a significant healthcare-associated pathogen due to its multidrug-resistant nature. Ongoing constraints in the discovery and provision of new antifungals create an urgent imperative to design effective remedies to this pressing global blight. Herein, we screened a chemical library and identified aryl-carbohydrazide analogs with potent activity against both and the most prevalent human fungal pathogen, . SPB00525 ['-(2,6-dichlorophenyl)-5-nitro-furan-2-carbohydrazide] exhibited potent activity against different strains that were resistant to standard antifungals. Using drug-induced haploinsufficient profiling, transcriptomics and metabolomic analysis, we uncovered that Ole1, a Δ(9) fatty acid desaturase, is the likely target of SPB00525. An analog of the latter, HTS06170 ['-(2,6-dichlorophenyl)-4-methyl-1,2,3-thiadiazole-5-carbohydrazide], had a superior antifungal activity against both and . Both SPB00525 and HTS06170 act as antivirulence agents and inhibited the invasive hyphal growth and biofilm formation of . SPB00525 and HTS06170 attenuated fungal damage to human enterocytes and ameliorate the survival of larvae used as systemic candidiasis model. These data suggest that inhibiting fungal Δ(9) fatty acid desaturase activity represents a potential therapeutic approach for treating fungal infection caused by the superbug and the most prevalent human fungal pathogen, .

To evaluate the antifungal activity of mangiferin against spp. resistant to fluconazole. The antifungal activity of mangiferin was assessed using broth microdilution and its interaction with azoles and amphotericin B was evaluated by checkerboard. The activity of mangiferin against spp. biofilms was assessed using the MTT colorimetric assay and its possible mechanism of action was evaluated using flow cytometry. Mangiferin showed activity against and resistant to fluconazole and showed synergism with azoles and amphotericin B. Mangiferin increased the activity of antifungals against biofilms and caused depolarization of the mitochondrial membrane and externalization of phosphatidylserine, suggesting apoptosis. mangiferin combined with antifungals has potential against spp.