Polyene-Based Derivatives with Antifungal Activities.

Polyenes are a class of organic compounds well known for their potent antifungal properties. They are effective due to their ability to target and disrupt fungal cell membranes by binding to ergosterol and forming pores. Despite their effectiveness as antifungal drugs, polyenes have several limitations, such as high toxicity to the host cell and poor solubility in water. This has prompted ongoing research to develop safer and more efficient derivatives to overcome such limitations while enhancing their antifungal activity. In this review article, we present a thorough analysis of polyene derivatives, their structural modifications, and their influence on their therapeutic effects against various fungal strains. Key studies are discussed, illustrating how structural modifications have led to improved antifungal properties. By evaluating the latest advancements in the synthesis of polyene derivatives, we highlight that incorporating amide linkers at the carboxylic moiety of polyene molecules notably improves their antifungal properties, as evidenced by derivatives 4, 5, 6G, and 18. This review can help in the design and development of novel polyene-based compounds with potent antifungal activities.

Quantum mechanics of particles constrained to spiral curves with application to polyene chains.

CONTEXT: Due to advances in synthesizing lower-dimensional materials, there is the challenge of finding the wave equation that effectively describes quantum particles moving on 1D and 2D domains. Jensen and Koppe and Da Costa independently introduced a confining potential formalism showing that the effective constrained dynamics is subjected to a scalar geometry-induced potential; for the confinement to a curve, the potential depends on the curve's curvature function. METHOD: To characterize the π electrons in polyenes, we follow two approaches. First, we utilize a weakened Coulomb potential associated with a spiral curve. The solution to the Schrödinger equation with Dirichlet boundary conditions yields Bessel functions, and the spectrum is obtained analytically. We employ the particle-in-a-box model in the second approach, incorporating effective mass corrections. The π - π ∗ transitions of polyenes were calculated in good experimental agreement with both approaches, although with different wave functions.

Tackling multi-drug resistant fungi by efflux pump inhibitors.

The emergence of multidrug-resistant fungi is of grave concern, and its infections are responsible for significant deaths among immunocompromised patients. The treatment of fungal infections primarily relies on a clinical class of antibiotics, including azoles, polyenes, echinocandins, polyketides, and a nucleotide analogue. However, the incidence of fungal infections is increasing as the treatment for human and plant fungal infections overlaps with antifungal drugs. The need for new antifungal agents acting on different targets than known targets is undeniable. Also, the pace at which loss of fungal susceptibility to antibiotics cannot be undermined. There are several modes by which fungi can develop resistance to antibiotics, including reduced drug uptake, drug target alteration, and a reduction in the cellular concentration of the drug due to active extrusions and biofilm formation. The efflux pump's overexpression in the fungi primarily reduced the antibiotic's concentration to a sub-lethal concentration, thus responsible for developing resistant fungus strains. Several strategies are used to check antibiotic resistance in multi-drug resistant fungi, including synthesizing antibiotic analogs and giving antibiotics in combination therapies. Among them, the efflux pump protein inhibitors are considered potential adjuvants to antibiotics and can block the efflux of antibiotics by inhibiting efflux pump protein transporters. Moreover, it can sensitize the antifungal drugs to multi-drug resistant fungi with overexpressed efflux pump proteins. This review discusses the natural lead molecules, repurposable drugs, and formulation strategies to overcome the efflux pump activity in the fungi.

Theoretical Insight into Psittacofulvins and Their Derivatives.

Psittacofulvins are polyenal dyes responsible for coloring parrot feathers and protecting them against photo-oxidation, harmful radicals, and bacterial degradation. To explain the unusual properties of these compounds, the thermodynamic and global chemical activity descriptors characterizing four natural and three synthetic psittacofulvins, as well as their hydroxyl, carboxyl and dialdehyde derivatives, were determined. To this aim, the DFT method at the B3LYP/QZVP theory level and the C-PCM solvation model were used. The calculations enabled the selection of the projected compounds for the greatest bioactivity and potential applicability as multifunctional ingredients in medicines, cosmetics, supplements, and food, in which they may play a triple role as preservative, radical scavenger, and coloring agent. The results obtained provide arguments for the identification of a fifth psittacofulvin within the parrot feather pigment, characterized by ten conjugated double bonds (docosadecaenal).

Molecular Mechanisms Associated with Antifungal Resistance in Pathogenic Candida Species.

Candidiasis is a highly pervasive infection posing major health risks, especially for immunocompromised populations. Pathogenic Candida species have evolved intrinsic and acquired resistance to a variety of antifungal medications. The primary goal of this literature review is to summarize the molecular mechanisms associated with antifungal resistance in Candida species. Resistance can be conferred via gain-of-function mutations in target pathway genes or their transcriptional regulators. Therefore, an overview of the known gene mutations is presented for the following antifungals: azoles (fluconazole, voriconazole, posaconazole and itraconazole), echinocandins (caspofungin, anidulafungin and micafungin), polyenes (amphotericin B and nystatin) and 5-fluorocytosine (5-FC). The following mutation hot spots were identified: (1) ergosterol biosynthesis pathway mutations (ERG11 and UPC2), resulting in azole resistance; (2) overexpression of the efflux pumps, promoting azole resistance (transcription factor genes: tac1 and mrr1; transporter genes: CDR1, CDR2, MDR1, PDR16 and SNQ2); (3) cell wall biosynthesis mutations (FKS1, FKS2 and PDR1), conferring resistance to echinocandins; (4) mutations of nucleic acid synthesis/repair genes (FCY1, FCY2 and FUR1), resulting in 5-FC resistance; and (5) biofilm production, promoting general antifungal resistance. This review also provides a summary of standardized inhibitory breakpoints obtained from international guidelines for prominent Candida species. Notably, N. glabrata, P. kudriavzevii and C. auris demonstrate fluconazole resistance.

Reactive oxidant species induced by antifungal drugs: identity, origins, functions, and connection to stress-induced cell death.

Reactive oxidant species (ROS) are unstable, highly reactive molecules that are produced by cells either as byproducts of metabolism or synthesized by specialized enzymes. ROS can be detrimental, e.g., by damaging cellular macromolecules, or beneficial, e.g., by participating in signaling. An increasing body of evidence shows that various fungal species, including both yeasts and molds, increase ROS production upon exposure to the antifungal drugs currently used in the clinic: azoles, polyenes, and echinocandins. However, the implications of these findings are still largely unclear due to gaps in knowledge regarding the chemical nature, molecular origins, and functional consequences of these ROS. Because the detection of ROS in fungal cells has largely relied on fluorescent probes that lack specificity, the chemical nature of the ROS is not known, and it may vary depending on the specific fungus-drug combination. In several instances, the origin of antifungal drug-induced ROS has been identified as the mitochondria, but further experiments are necessary to strengthen this conclusion and to investigate other potential cellular ROS sources, such as the ER, peroxisomes, and ROS-producing enzymes. With respect to the function of the ROS, several studies have shown that they contribute to the drugs' fungicidal activities and may be part of drug-induced programmed cell death (PCD). However, whether these "pro-death" ROS are a primary consequence of the antifungal mechanism of action or a secondary consequence of drug-induced PCD remains unclear. Finally, several recent studies have raised the possibility that ROS induction can serve an adaptive role, promoting antifungal drug tolerance and the evolution of drug resistance. Filling these gaps in knowledge will reveal a new aspect of fungal biology and may identify new ways to potentiate antifungal drug activity or prevent the evolution of antifungal drug resistance.

An overview of opportunistic fungal infections associated with COVID-19.

The COVID-19 survivors and long-term steroid administered patients exhibit a variety of fungal co-infections. The lives of COVID-19 patients and survivors are hampered by fungal species of the genera Candida, Aspergillus, and Mucor. There have been cases of mucormycosis, aspergillosis, and candidiasis in COVID-19 patients. The treatments given to these opportunistic fungal infections include polyene like amphotericin B, azoles including imidazoles like ketoconazole, miconazole, and triazoles like fluconazole, voriconazole, itraconazole, Echinocandin derivatives like- caspofungin, micafungin, immunomodulatory therapy, granulocyte transfusion, etc. A successful recovery and the reduction of fatalities depend on prompt diagnosis and treatment. To reduce mortality, advanced techniques to identify such uncommon infections at a very early stage are necessary. This review's goal is to provide a summary of the systemic and superficial opportunistic fungal infections that the COVID-19 survivors were dealing with, including information on illness incidence, pathogenicity, and treatment.

Geometric Isomerisation of Bifunctional Alkenyl Fluoride Linchpins: Stereodivergence in Amide and Polyene Bioisostere Synthesis.

Amide groups are pervasive across the chemical space continuum, where their structural and pharmacological importance, juxtaposed with the hydrolytic vulnerabilities, continues to fuel bioisostere development. Alkenyl fluorides have a venerable history as effective mimics (Ψ[CF=CH]) owing to the planarity of the motif and intrinsic polarity of the C(sp2 )-F bond. However, emulating the s-cis to the s-trans isomerisation of a peptide bond with fluoro-alkene surrogates remains challenging, and current synthetic solutions only enable access to a single configuration. Through the design of an ambiphilic linchpin based on a fluorinated ß-borylacrylate, it has been possible to leverage energy transfer catalysis to affect this unprecedented isomerisation process: this provides geometrically-programmable building blocks that can be functionalised at either terminus. Irradiation at λmax =402 nm with inexpensive thioxanthone as a photocatalyst enables rapid, effective isomerisation of tri- and tetra-substituted species (up to E/Z 98 : 2 in 1 h), providing a stereodivergent platform for small molecule amide and polyene isostere discovery. Application of the methodology in target synthesis and initial laser spectroscopic studies are disclosed together with crystallographic analyses of representative products.

The challenges of the genome-based identification of antifungal resistance in the clinical routine.

The increasing number of chronic and life-threatening infections caused by antimicrobial resistant fungal isolates is of critical concern. Low DNA sequencing cost may facilitate the identification of the genomic profile leading to resistance, the resistome, to rationally optimize the design of antifungal therapies. However, compared to bacteria, initiatives for resistome detection in eukaryotic pathogens are underdeveloped. Firstly, reported mutations in antifungal targets leading to reduced susceptibility must be extensively collected from the literature to generate comprehensive databases. This information should be complemented with specific laboratory screenings to detect the highest number possible of relevant genetic changes in primary targets and associations between resistance and other genomic markers. Strikingly, some drug resistant strains experience high-level genetic changes such as ploidy variation as much as duplications and reorganizations of specific chromosomes. Such variations involve allelic dominance, gene dosage increments and target expression regime effects that should be explicitly parameterized in antifungal resistome prediction algorithms. Clinical data indicate that predictors need to consider the precise pathogen species and drug levels of detail, instead of just genus and drug class. The concomitant needs for mutation accuracy and assembly quality assurance suggest hybrid sequencing approaches involving third-generation methods will be utilized. Moreover, fatal fast infections, like fungemia and meningitis, will further require both sequencing and analysis facilities are available in-house. Altogether, the complex nature of antifungal resistance demands extensive sequencing, data acquisition and processing, bioinformatic analysis pipelines, and standard protocols to be accomplished prior to genome-based protocols are applied in the clinical setting.

Integrating Regioselective E→Z Isomerization of Trienones with Cascade Sequences under Photosensitizer-Free Direct Irradiation at 390†nm.

The regioselective E→Z isomerization of a target olefin unit embedded in a conjugated polyene is challenging. Examples are limited to retinal and its derivatives only. The problem is further amplified when such an isomerization is integrated into cascade sequences, among which the regioselectivity and subsequent directionality are the major bottlenecks. Indeed, there are no reports till date for such a transformation. Herein, it is reported that such a controlled isomerization and subsequent cyclization cascade can be enabled by photosensitizer-free direct irradiation of linearly conjugated acyclic polyenes in dichloromethane solvent using a 390 nm LED. The directionality results from deconjugation of the extended π-system in the transient Z-isomer due to stabilizing n→π* interactions between 1,4-dicarbonyls (C=O→C=O) or 1,4-carbonyl/-aryl (C=O→aryl) groups. The involvement of such noncovalent interactions has been supported by X-ray crystallography and control experiments. Thus, conjugated trienones can be stereoselectively converted into oxabicyclo[3.2.1]octadienes in an atom- and step-economic manner, including the first example by regioselective isomerization of a tetrasubstituted alkene. The reaction conditions are very general (>46 examples). The reaction can be conducted under open air atmosphere at ambient temperature. Such a cascade cyclization can also be realized in solid state.

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.

Reversing the Bond Length Alternation Order in Conjugated Polyenes by Substituent Effects.

We have synthesised several push-pull substituted conjugated polyenes and determined their accurate C-C bond lengths and charge-density distributions by utilising quantum crystallographic techniques. In a series of alkene, dienes, and triene bearing two (trifluoromethyl)sulfonyl (triflyl) groups on the terminal carbon atom, unique reversal of the bond-length alternation (BLA) order has been observed. This is a pronounced aberration from the molecular structure predicted by the Lewis-structure-based neutral resonance structure. Such reversal of BLA order has not been observed in push-pull compounds bearing conventional electron-withdrawing groups such as carbonyl and cyano groups instead of triflyl groups. Bonding behaviour of both normal and reversed bond length alternating systems has been revealed by complementary bonding analysis using several bond descriptors based on the experimentally fitted wavefunctions.

Three new long-chain polyenes from the mangrove-derived fungus Penicillium herquei JX4.

One new epimer pair of long-chain polyenes penicilqueis E (1) and F (2), and one new long-chain polyene pinophol G (3), along with one known compound (4), were obtained from EtOAc extract of the mangrove-derived fungus Penicillium herquei JX4. Their structures were elucidated by detailed analysis of comprehensive spectroscopic data. The inhibitory activities of all compounds against the nitric oxide (NO) production induced by lipopolysaccharide in mouse macrophage RAW 264.7 cells in vitro were evaluated.

Cytochrome†P450 Catalyzes Benzene Ring Formation in the Biosynthesis of Trialkyl-Substituted Aromatic Polyketides.

Lorneic acid and related natural products are characterized by a trialkyl-substituted benzene ring. The formation of the aromatic core in the middle of the polyketide chain is unusual. We characterized a cytochrome P450 enzyme that can catalyze the hallmark benzene ring formation from an acyclic polyene substrate through genetic and biochemical analysis. Using this P450 as a beacon for genome mining, we obtained 12 homologous type I polyketide synthase (PKS) gene clusters, among which two gene clusters are activated and able to produce trialkyl-substituted aromatic polyketides. Quantum chemical calculations were performed to elucidate the plausible mechanism for P450-catalyzed benzene ring formation. Our work expands our knowledge of the catalytic diversity of cytochrome P450.

Epigenetic Regulation of Antifungal Drug Resistance.

In medical mycology, epigenetic mechanisms are emerging as key regulators of multiple aspects of fungal biology ranging from development, phenotypic and morphological plasticity to antifungal drug resistance. Emerging resistance to the limited therapeutic options for the treatment of invasive fungal infections is a growing concern. Human fungal pathogens develop drug resistance via multiple mechanisms, with recent studies highlighting the role of epigenetic changes involving the acetylation and methylation of histones, remodeling of chromatin and heterochromatin-based gene silencing, in the acquisition of antifungal resistance. A comprehensive understanding of how pathogens acquire drug resistance will aid the development of new antifungal therapies as well as increase the efficacy of current antifungals by blocking common drug-resistance mechanisms. In this article, we describe the epigenetic mechanisms that affect resistance towards widely used systemic antifungal drugs: azoles, echinocandins and polyenes. Additionally, we review the literature on the possible links between DNA mismatch repair, gene silencing and drug-resistance mechanisms.

Postantifungal Effect of Antifungal Drugs against Candida: What Do We Know and How Can We Apply This Knowledge in the Clinical Setting?

The study of the pharmacological properties of an antifungal agent integrates the drug pharmacokinetics, the fungal growth inhibition, the fungicidal effect and the postantifungal activity, laying the basis to guide optimal dosing regimen selection. The current manuscript reviews concepts regarding the postantifungal effect (PAFE) of the main classes of drugs used to treat Candida infections or candidiasis. The existence of PAFE and its magnitude are highly dependent on both the fungal species and the class of the antifungal agent. Therefore, the aim of this article was to compile the information described in the literature concerning the PAFE of polyenes, azoles and echinocandins against the Candida species of medical interest. In addition, the mechanisms involved in these phenomena, methods of study, and finally, the clinical applicability of these studies relating to the design of dosing regimens were reviewed and discussed. Additionally, different factors that could determine the variability in the PAFE were described. Most PAFE studies were conducted in vitro, and a scarcity of PAFE studies in animal models was observed. It can be stated that the echinocandins cause the most prolonged PAFE, followed by polyenes and azoles. In the case of the triazoles, it is worth noting the inconsistency found between in vitro and in vivo studies.

Polyene Antibiotics Physical Chemistry and Their Effect on Lipid Membranes; Impacting Biological Processes and Medical Applications.

This review examined a collection of studies regarding the molecular properties of some polyene antibiotic molecules as well as their properties in solution and in particular environmental conditions. We also looked into the proposed mechanism of action of polyenes, where membrane properties play a crucial role. Given the interest in polyene antibiotics as therapeutic agents, we looked into alternative ways of reducing their collateral toxicity, including semi-synthesis of derivatives and new formulations. We follow with studies on the role of membrane structure and, finally, recent developments regarding the most important clinical applications of these compounds.

Therapeutic Approaches for Combating Aspergillus Associated Infection.

Now-a-days fungal infection emerges as a significant problem to healthcare management systems due to high frequency of associated morbidity, mortality toxicity, drug-drug interactions, and resistance of the antifungal agents. Aspergillus is the most common mold that cause infection in immunocompromised hosts. It's a hyaline mold that is cosmopolitan and ubiquitous in nature. Aspergillus infects around 10 million population each year with a mortality rate of 30-90%. Clinically available antifungal formulations are restricted to four classes (i.e., polyene, triazole, echinocandin, and allylamine), and each of them have their own limitations associated with the activity spectrum, the emergence of resistance, and toxicity. Consequently, novel antifungal agents with modified and altered chemical structures are required to combat these invasive fungal infections. To overcome these limitations, there is an urgent need for new antifungal agents that can act as potent drugs in near future. Currently, some compounds have shown effective antifungal activity. In this review article, we have discussed all potential antifungal therapies that contain old antifungal drugs, combination therapies, and recent novel antifungal formulations, with a focus on the Aspergillus associated infections.

Repurposing Antifungals for Host-Directed Antiviral Therapy?

Because of their epidemic and pandemic potential, emerging viruses are a major threat to global healthcare systems. While vaccination is in general a straightforward approach to prevent viral infections, immunization can also cause escape mutants that hide from immune cell and antibody detection. Thus, other approaches than immunization are critical for the management and control of viral infections. Viruses are prone to mutations leading to the rapid emergence of resistant strains upon treatment with direct antivirals. In contrast to the direct interference with pathogen components, host-directed therapies aim to target host factors that are essential for the pathogenic replication cycle or to improve the host defense mechanisms, thus circumventing resistance. These relatively new approaches are often based on the repurposing of drugs which are already licensed for the treatment of other unrelated diseases. Here, we summarize what is known about the mechanisms and modes of action for a potential use of antifungals as repurposed host-directed anti-infectives for the therapeutic intervention to control viral infections.

Recent Perspectives in the Management of Fungal Keratitis.

Mycotic keratitis is common in warm, humid regions with a varying profile of pathogenic fungi according to geographical origin, socioeconomic status, and climatic condition. Clinical diagnosis can be challenging in difficult cases and those refractory to treatment. Fungal hyphae on microscopic examination and culture isolation have been the gold standard in the laboratory diagnosis of fungal keratitis. A culture isolate of the aetiological fungus is essential to perform antifungal susceptibility testing. As the culture isolation of fungi is time-consuming, causing delays in the initiation of treatment, newer investigative modalities such as in vivo confocal microscopy and molecular diagnostic methods have recently gained popularity. Molecular diagnostic techniques now help to obtain a rapid diagnosis of fungal keratitis. Genomic approaches are based on detecting amplicons of ribosomal RNA genes, with internal transcribed spacers being increasingly adopted. Metagenomic deep sequencing allows for rapid and accurate diagnosis without the need to wait for the fungus to grow. This is also helpful in identifying new emerging strains of fungi causing mycotic keratitis. A custom-tear proteomic approach will probably play an important diagnostic role in future in the management of mycotic keratitis. Positive repeat cultures are being suggested as an important gauge indicative of a poor prognosis. Positive repeat fungal cultures help to modify a treatment regimen by increasing its frequency, providing the addition of another topical and oral antifungal agent along with close follow-up for perforation and identifying need for early therapeutic keratoplasty. The role of collagen crosslinking in the treatment of fungal keratitis is not convincingly established. Rapid detection by multiplex PCR and antifungal susceptibility testing of the pathogenic fungi, adopted into a routine management protocol of fungal keratitis, will help to improve treatment outcome. Early therapy is essential in minimizing damage to the corneal tissue, thereby providing a better outcome. The role of conventional therapy with polyenes, systemic and targeted therapy of antifungal agents, newer azoles and echinocandins in fungal keratitis has been widely studied in recent times. Combination therapy can be more efficacious in comparison to monotherapy. Given the diversity of fungal aetiology, the emergence of new corneal pathogenic fungi with varying drug susceptibilities, increasing the drug resistance to antifungal agents in some genera and species, it is perhaps time to adopt recent molecular methods for precise identification and incorporate antifungal susceptibility testing as a routine.