Treatment Of Fungal Infections Research Articles

Novel Triazoles with Potent and Broad-Spectrum Antifungal Activity In Vitro and In Vivo.

Triazoles have demonstrated significant efficacy in the treatment of fungal infections. However, increasing drug resistance is a growing concern that negatively impacts their effectiveness. By designing a well-crafted side chain, triazoles can be endowed with advantages, like higher potency and the ability to overcome drug resistance. This highlights the diverse interactions between side chains and CYP51. To explore novel triazole antifungal agents, we synthesized three series of fluconazole-core compounds and focused on optimizing the chain based on molecule docking and in vitro results. The most potent S-F24 exhibited excellent broad-spectrum antifungal activity that was better or comparable to clinically used azoles. S-F24 maintained its potency even against multi-resistant Candida albicans. Additionally, S-F24 displayed a good safety profile with high selectivity, low hemolytic effects, and low tendency to induce resistance. Our findings collectively demonstrated that there was still a high potential for side-chain modification in the development of novel azoles.

Recent drug development and treatments for fungal infections.

Fungal infections are now becoming a hazard to individuals which has paved the way for research to expand the therapeutic options available. Recent advances in drug design and compound screening have also increased the pace of the development of antifungal drugs. Although several novel potential molecules are reported, those discoveries have yet to be translated from bench to bedside. Polyenes, azoles, echinocandins, and flucytosine are among the few antifungal agents that are available for the treatment of fungal infections, but such conventional therapies show certain limitations like toxicity, drug interactions, and the development of resistance which limits the utility of existing antifungals, contributing to significant mortality and morbidity. This review article focuses on the existing therapies, the challenges associated with them, and the development of new therapies, including the ongoing and recent clinical trials, for the treatment of fungal infections. Advancements in antifungal treatment: a graphical overview of drug development, adverse effects, and future prospects.

The Siderophore Ferricrocin Mediates Iron Acquisition in Aspergillus fumigatus.

The opportunistic fungal pathogen Aspergillus fumigatus utilizes two high-affinity iron uptake mechanisms, termed reductive iron assimilation (RIA) and siderophore-mediated iron acquisition (SIA). The latter has been shown to be crucial for virulence of this fungus and is a target for development of novel strategies for diagnosis and treatment of fungal infections. So far, research on SIA in this mold focused mainly on the hyphal stage, revealing the importance of extracellular fusarinine-type siderophores in iron acquisition as well as of the siderophore ferricrocin in intracellular iron handling. The current study aimed to characterize iron acquisition during germination. High expression of genes involved in biosynthesis and uptake of ferricrocin in conidia and during germination, independent of iron availability, suggested a role of ferricrocin in iron acquisition during germination. In agreement, (i) bioassays indicated secretion of ferricrocin during growth on solid media during both iron sufficiency and limitation, (ii) ferricrocin was identified in the supernatant of conidia germinating in liquid media during both iron sufficiency and limitation, (iii) in contrast to mutants lacking all siderophores, mutants synthesizing ferricrocin but lacking fusarinine-type siderophores were able to grow under iron limitation in the absence of RIA, and (iv) genetic inactivation of the ferricrocin transporter Sit1 decreased germination in the absence of RIA. Taken together, this study revealed that ferricrocin has not only an intracellular role but also functions as an extracellular siderophore to support iron acquisition. The iron availability-independent ferricrocin secretion and uptake during early germination indicate developmental, rather than iron regulation. IMPORTANCE Aspergillus fumigatus is one of the most common airborne fungal pathogens for humans. Low-molecular-mass iron chelators, termed siderophores, have been shown to play a central role in iron homeostasis and, consequently, virulence of this mold. Previous studies demonstrated the crucial role of secreted fusarinine-type siderophores, such as triacetylfusarinine C, in iron acquisition, as well as of the ferrichrome-type siderophore ferricrocin in intracellular iron storage and transport. Here, we demonstrate that ferricrocin is also secreted to mediate iron acquisition during germination together with reductive iron assimilation. During early germination, ferricrocin secretion and uptake were not repressed by iron availability, indicating developmental regulation of this iron acquisition system in this growth phase.

Decomposition of Fungus Chytrid

The purpose of this study was to look into the negative effects of the fungus chytrid as a microorganism. The research question was whether these organisms could be separated from eukaryotic life such as plants. The method involved using terbinafine as a treatment for fungal infections. The process consisted of adding antifungal granules to the source of the infestation. The result showed a terbinae with a volume of 10g and a concentration of 1% w/w that effectively separated the fungi from the plant. It concluded the active content of terbinafine was the hydrochloride addition of hydrogen to a chytrid fungus

Antibacterial and Antifungal Activities of Avicennia marina Extract Against Various Multiple Drug Resistant Microorganisms

Avicennia marina is a commonly found mangrove species in coastal regions, and is known for its medicinal properties. In this study, the antibacterial and antifungal activities of ethanolic extract of Avicennia marina leaves were evaluated against MDR microorganisms. The antimicrobial activity of the extract was assessed against a range of bacterial strains, including Salmonella sp. (MDR), Klebsiella sp. (MDR), Pseudomonas sp. (MDR), Acinetobacter sp. (MDR), Staphylococcus aureus as well as the fungal strain Candida albicans (ATCC 10231), Candida parapsilosis (ATCC 22019). The results showed that the leaf extracts of Avicennia marina exhibited significant antimicrobial activity against all tested MDR microorganisms. The phytochemical content of the plant includes many bioactive compounds - flavonoids, tannins, and alkaloids, which may be responsible for the observed antimicrobial activities. These findings suggest that Avicennia marina may be a potential source of natural antimicrobial agents, which could be used to develop new drugs for the treatment of resistant bacterial and fungal infections. Further studies are needed to identify and isolate the active compounds responsible for the observed activity and to evaluate their efficacy and safety in vivo.

Formulation Perspectives in Topical Antifungal Drug Therapy: A Review

Topical medication delivery is the process of directly treating a cutaneous ailment or the cutaneous manifestation of a general disease by applying a pharmaceutical dosage form to the skin with the goal of reducing the drug's pharmacological or other effects to the surface of skin. A wide range of pharmacological dosage forms, such as semisolids, liquid preparations, sprays, solid powders, gels, creams, and ointments, are used in topical drug delivery systems. A gel is a cross-linked polymer network swollen in a liquid medium. Its properties depend strongly on the interaction between solid state polymer and the liquid component. Gels don't have a flow that is steady. An interlacing three-dimensional network of dispersed phase particles is created by the interaction of the polymer and the liquid dispersion medium. Because topical gel formulations are less oily and readily removed from the skin, they provide an effective medication delivery mechanism. Compared to cream and ointments, gel composition offers greater application properties and stability. One of the most frequent issues with dermatological problems is fungal infection of the skin. The most effective option for treating cutaneous infections is topical treatment. The most popular antifungals in the treatment of both local and systemic fungal infections are azoles. The benefits of topical treatment for fungal infections include less risk of systemic adverse effects and medications that are targeted to the infection site. Important actions for boosting treatment effectiveness include formulation design and optimization. The most helpful aspects of a topical medication delivery system are the medication's physiochemical characteristics and formulation type. As a result, some recent developments in formulation have been researched for the delivery of antifungal medications via the target region of the skin. This review focuses on the research that has been done so far on antifungal gel and a thorough analysis of it.
 Keywords: Topical gel, Antifungal, Drug delivery, dispersion medium, fungal infection, adverse effects

Comparative assessment of solubility enhancement of itroconazole by solid dispersion and co-crystallization technique: Investigation of simultaneous effect of media composition on drug dissolution

Solubility of the drug is an important property of the drug as it affects the release, absorption, dissolution rate and ultimately bioavailability of the drug. Hence, the poorly aqueous soluble drug, need to be processed, to enhance its solubility and dissolution. The Biopharmaceutical System of Classification (BCS) II drugs are poorly soluble and have high permeability. Though their good ability to permeate through the membrane make them clinically useful but the problem associated with the solubility restrict their clinical use. Therefore, there is need to improve the solubility of such drug molecules to get effective pharmacological action. Itraconazole (ITZ) is an antifungal agent used in the treatment of fungal infections having poor aqueous solubility as belonging to BCS class II. The present study was aim to enhance the solubility of ITZ by solid dispersion and co-crystallization techniques. Investigation of simultaneous effect of media composition on drug dissolution was also the objective of this work. The ITZ-SD and ITZ-CCs were prepared from ITZ and other excipients like PEG 4000, oxalic acid, fumaric and malic acid by solvent evaporation, kneading technique, slurry conversion and solvent drop grinding methods. The prepared ITZ-SD, ITZ-OA-CCs, ITZ-FA-CCs and ITZ-MA-CCs were evaluated for FTIR, DSC, PXRD, % yield, micromeritic properties. The optimized ITZ-SD and ITZ-CCs were used to compress a tablet and subject to post-compression parameters. The results of FTIR and DSC showed the absence of interaction between the drug and excipients. The PXRD pattern demonstrated the formation of crystalline structures with 6 folds increased in solubility during saturation solubility analysis. In vitro dissolution was carried out in dissolution media with different pH which shows the maximum release from ITZ-SD and ITZ-CCs in pH 6.8. This also revealed the highly pH dependent solubility and dissolution behavior of the weakly basic BCS class II drug (ITZ) with pKa value of 3.7. The overall results in this study indicated the potential of solid dispersion and co-crystals for enhancement of solubility of the poorly water-soluble drugs.

Diagnosis and Treatment of Fungal Infections in Lung Transplant Recipients.

Fungal infections are a significant source of morbidity in the lung transplant population via direct allograft damage and predisposing patients to the development of chronic lung allograft dysfunction. Prompt diagnosis and treatment are imperative to limit allograft damage. This review article discusses incidence, risk factors, and symptoms with a specific focus on diagnostic and treatment strategies in the lung transplant population for fungal infections caused by Aspergillus, Candida, Coccidioides, Histoplasma, Blastomyces, Scedosporium/Lomentospora, Fusarium, and Pneumocystis jirovecii. Evidence for the use of newer triazole and inhaled antifungals to treat isolated pulmonary fungal infections in lung transplant recipients is also discussed.

Treatment and Outcomes of Fungal Prosthetic Joint Infections: A Systematic Review of 225 Cases

BackgroundFungal prosthetic joint infections (PJIs) after a total joint arthroplasty are a rare, yet severe, occurrence not often reported in the literature. Unlike in bacterial PJIs, no clear consensus exists on fungal PJI optimal management. MethodsA systematic review was performed using the PubMed and Embase databases. Manuscripts were assessed for inclusion and exclusion criteria. The Strengthening the Reporting of Observational Studies in Epidemiology checklist was applied for quality assessment. Individual demographic, clinical, and treatment information was retrieved from included manuscripts. ResultsSeventy one patients who had a PJI of the hip and 126 of the knee were included. Infection recurrence occurred in 29.6% and 18.3% of patients with hip or knee PJI, respectively. Patients who had knee PJIs recurrence had a significantly higher Charlson Comorbidity Index (CCI). For knee PJIs, infection recurrence was more common in patients with Candida albicans (CA) PJIs (P = .022). Two-stage exchange arthroplasty was the most common procedure in both joints. Multivariate analysis found that CCI ≥ 3 was associated with an 18.5-fold increase in the risk of knee PJI recurrence (Odds ratio [OR] = 18.57). Additional risk factors for recurrence in the knee included CA etiology (OR = 3.56) and C-reactive protein at presentation ≥ 6 (OR = 6.54). Compared to debridement, antibiotics, and implant retention, 2-stage procedure was a protective factor for PJI recurrence in the knee (OR = 0.18). No risk factors were found in patients who had hip PJIs. ConclusionTreatment of fungal PJIs varies widely, but 2-stage revision is the most common. Risk factors for knee fungal PJI recurrence include elevated CCI, infection by CA, and high C-reactive protein at presentation.

Identification of effective plant extracts against candidiasis: an in silico and in vitro approach

BackgroundGlobally, millions of people suffer from repeated fungal infections affecting the skin, keratinized tissues, and mucosal membranes. Approximately 1.7 million cases result in death with an elevated incidence rate among immunocompromised people that may later result in severe infections. Among the causative agents, Candida albicans are the most prevalent fungi inducing subcutaneous to invasive candidiasis. Although they are commensals in human body alteration in gut or prolonged treatments results in candidiasis. Several virulence proteins of C. albicans are involved in infections and secreted aspartic proteases2 (SAP2) plays an important role among them by causing damage to the reconstituted human epithelium. In the present study, phytochemicals from Heliotropium indicum, Grona triflora, Ziziphus mauritiana, Atalantia racemosa, Coccinia grandis, Caryota urens, Aristolochia bracteolata, Evolvulus alsinoides, Pyrus communis and Commelina benghalensis were studied against SAP2 with the help of bioinformatic tools to understand their binding efficiency.ResultsThe phytochemical structures were retrieved from PubChem database and the target protein structure was retrieved from PDB database with ID:3PVK. ADME profiling for phytochemicals was performed with Qikprop module, followed by docking with protein using Schrodinger software. Docking studies showed that Indicine-N-Oxide from H. indicum scored the significant glide score of − 5.54 kcal/mol. Finally, antifungal studies against C. albicans were conducted using several extracts of plants containing phytochemicals with considerable glide scores on docking studies. The Ethyl acetate leaf extract of H. indicum prominently inhibited the fungal growth when compared with the control.ConclusionIdentification of effective therapeutic candidates for the treatment of fungal infection is facilitated by the potential of H. indicum to hinder fungal growth and the interaction of their phytocompounds with fungal targets paves a way for developing a novel drug.

KETOCONAZOLE LADEN MICROEMULSION BASED GEL FORMULATION AGAINST SKIN FUNGAL INFECTION

Objective: The present research was aimed to develop ketoconazole (KT) loaded microemulsion-based gel formulation for effective topical delivery through enhanced drug solubility, improved skin permeation and reduced side effects overcoming drawbacks of conventional dosage forms. Methods: For the selection of oil, surfactant and co-surfactant mixture (Smix) ratio, the phase titration method was used and pseudo-ternary phase diagrams were prepared. D-optimal mixture design was employed to optimize the microemulsion system taking oil, Smix and water as independent variables and particle size, polydispersity index, zeta potential, % transmittance and cumulative % drug release as response variables. Finally, topical gel formulation of KT-loaded microemulsion was developed and evaluated for physico-chemical properties, rheological properties, in vitro drug release kinetics and ex-vivo drug permeation. Results: The optimized microemulsion was found to be a transparent formulation with 19.7 nm particle size, 0.268 polydispersity index,-0.2 mV zeta potential, 97.83% transmittance and 85.85% cumulative drug release at 24 h. The developed gel of optimized microemulsion possessed pH 6.20, viscosity 2178 cps, spreadability 18.634 g.cm2/sec, adhesiveness 45.989 N/mm2, and cohesiveness-85.583. The in vitro drug release was found to be 69.08 % (at 24 h), showing sustained release and Higuchi kinetic profile. The developed gel exhibited 1.84-fold higher drug permeation flux as compared to the marketed product. Conclusion: The developed gel formulation possessed all desired quality attributes and physico-chemical properties. The in vitro and ex-vivo study data proved it’s suitability as a better alternative to conventional products in the effective treatment of fungal skin infections.

Synergistic Interactions between Linalool and Some Antimycotic Agents against Candida spp. as a Basis for Developing New Antifungal Preparations

The incidence of superficial infections, including oral candidiasis, has recently increased significantly. Their treatment is quite difficult due to the growing resistance of Candida spp. to antifungal agents. Therefore, it is necessary to search for novel antimycotics or alternative antifungal therapies. The purpose of the study was to evaluate the antifungal activity of natural terpene—linalool (LIN)—against both reference fungi belonging to yeasts and Candida spp. isolates from the oral cavities of immunocompromised, hemato-oncology patients. Moreover, its mechanism of action and interactions with selected antifungal drugs or antiseptics were investigated. The broth microdilution technique, ergosterol or sorbitol tests, and a checkerboard method were used for individual studies. The LIN showed potential activity toward studied strains of fungi with a minimal inhibitory concentration (MIC) in the range of 0.5–8 mg/mL and fungicidal effect. This compound was also found to bind to ergosterol in the yeast cell membrane. Additionally, the interactions between LIN with antiseptics such as chlorhexidine, cetylpyridinium, and triclosan showed beneficial synergistic effect (with FIC = 0.3125–0.375), or an additive effect with silver nitrate and chlorquinaldol (FIC = 0.625–1). Moreover, statistically significant differences in MIC values were found for the synergistic combinations of LIN. No interaction was indicated for nystatin. These results confirm that the LIN seems to be a promising plant component used alone or in combination with other antimycotics in the prevention and treatment of superficial fungal infections. However, further clinical trials are required.

Antimicrobial potential of phytocompounds of Acorus calamus: in silico approach

Medicinal plants are used from prehistoric time to cure various life-threatening bacterial diseases. Acorus calamus is an important medicinal plant widely used to cure gastrointestinal, respiratory, kidney and liver disorders. The objective of the current research was to investigate the interaction of major phytoconstituents of Acorus calamus with bacterial (6VJE) and fungal (1EA1) protein targets. Protein-ligand interactions were estimated using the AutoDock software, drug likeness was predicted by using the molinspiration server and toxicity was predicted with the swissADME and protox II servers. MD simulation of phytocompounds with the best profiles was done on the GROMACS software for 100 ns. Molecular docking results showed among all the selected major phytoconstituents, that β-cadinene showed best binding interaction in complex with bacterial (6VJE) and fungal (1EA1) protein targets with binding energy −7.66 ± 0.1 and −7.73 ± 0.15 kcal mol−1, respectively. Drug likeness and toxicity predictions showed that β-cadinene follows all rules of drug likeness and toxicity. MD simulation study revealed that β-cadinene fit in binding pocket of bacterial and fungal targets and found to be stable throughout the duration of the simulation. Based on the observations from this in-silico study it is being proposed that β-cadinene, a major phytocompound of Acorus calamus, can be considered for the treatment of bacterial and fungal infections since the study shows that it might be one of the compounds that contributes majorly to the plant’s biological activity. This study needs in vitro and in vivo validation. Communicated by Ramaswamy H. Sarma

Naftifine: A Topical Allylamine for Superficial Dermatophytosis.

Dermatophytosis is a very common public health problem with high prevalence. Dermatophytes are a highly specialized set of filamentous fungi, which are adapted to keratinized tissues of humans and animals. Dermatophytosis is the most common fungal infection worldwide, affecting approximately 20-25% of the world's population. The etiological agents of dermatophytosis, called dermatophytes, change with geography and socioeconomic status. Trichophyton rubrum (T. rubrum) is the prime species for skin and nail infections followed by T. mentagrophytes/ T. interdigital complex. There is a shift from T. rubrum to T. mentagrophytes in India for superficial fungal infections. In order to deal with fungal infections, treatment strategies involve the use of systemic antifungals and/or topical antifungal agents. Naftifine is a synthetic allylamine antifungal first reported in 1974 and in 1985 became the first commercially available allylamine. The highly lipophilic nature of allylamine allows efficient penetration and reasonably high concentrations in the stratum corneum (SC) and hair follicles. Naftifine is fungicidal as well as fungistatic. The higher efficacy rates of allylamines over imidazoles for the treatment of fungal infections, even for months after cessation of treatment, is thought to be due to their fungicidal effect, as well as to potentially greater keratin binding and slower release from the SC. The effectiveness of naftifine is also demonstrated against various bacteria belonging to both gram-negative and gram-positive classes. The antiinflammatory property of naftifine has been reported in various preclinical studies where it has been shown to target the prostaglandin pathway. Naftifine 1 and 2% gel and cream is approved by The United States Food and Drug Administration (USFDA), recently naftifine has been approved in India by the Indian regulatory authority Drug Controller General of India (DCGI) for the treatment of dermatophytosis. Naftifine 2% also appears to be a promising treatment, requiring fewer applications than the 1% formulation. Naftifine appears to be effective in a single dose and has a shorter treatment duration than azoles. Naftifine demonstrated its efficacy and safety in various clinical studies of tinea infections. Naftifine offers a very useful and promising option for treating dermatophytosis.

Evaluation of liposomal hydrocolloidal NPs loaded by tea tree oil as antifungal agent in vitro and in vivo investigations: Preclinical studies

Fungi have a great ability and a wide variety of mechanisms to endure the toxicity of current antifungal agents. Researchers are working to find new therapeutic agents to combat the resistance ability of fungi. Almost all commercial antifungal agents have a wide variety of side effects on human health. This study aims to introduce tea tree oil nanoparticles as antifungal delivery termed TNSAD, which contains hybrid tea tree oil attached chitosan in a liposomal formulation, and assess its antifungal activity using in vitro and in vivo infection models. Tea tree oil was first coated by chitosan, then inserted inside liposomal bilayers, and finally functionalized by a layer of chitosan, forming the TNSAD. The antifungal activity was evaluated against four different invasive, opportunistic, and zoonotic fungal pathogens (Aspergillus flavus, Aspergillus fumigatus, Microsporum gypsum, and Fusarium oxysporum). The cytotoxicity of TNSAD was then tested against the HEp-2 cell line. Finally, the antifungal activity against Aspergillus fumigatus and Microsporum gypsum was assessed in vivo in a rat model. The in vitro results confirm the potency of TNSAD against fungi and its safety at a concentration of ≤ 5 mg/ml. In vivo results revealed that fungal cells were destroyed within the tissue when used systematically. we have described here a natural remarkable design that represents a potential antifungal agent and provided evidence for its efficiency and safety, which makes it a promising antifungal agent for the treatment of systemic and topical fungal infections.

Exploiting itraconazole-loaded nanomixed micelles in coated capsules as efficient colon-targeted delivery system for improved antifungal and potential anticancer efficacy

Chronic Inflammatory bowel diseases are usually accompanied by opportunistic colonic fungal infections. Itraconazole (ITZ), is a highly lipophilic broad-spectrum antifungal drug that is superiorly effective against several fungal species. Box-Behnken design was adopted to design ITZ-nanomixed micelles (ITZ-NMMs), aiming to enhance ITZ solubility, using various concentrations of Pluronic® L121, Cremophor EL, and with either sodium-deoxycholate or Pluronic® F68 through thin film hydration technique. Optimized formula composed of 90 % Pl–L121, 9.1% Cremophor EL, 3.127 % ITZ concentration and SDC as the hydrophilic surfactant and its particle size, Polydispersity index, zeta potential, entrapment efficiency, and release extent after 3 h were found to be 17.82 ± 0.189 nm, 0.26 ± 0.014, -6.72 ± 0.725 mV, 66 ± 7.4%, and 96.3 ± 7.22%, respectively. In vitro ITZ release study implied the ability of optimal ITZ-NMMs to enhance ITZ solubility in comparison to ITZ suspension. Also, augmented anti-fungal and anti-cancer activities were proven as ITZ-NMMs IC50 was 16.5 times that of pure ITZ. Afterwards, lyophilized optimal ITZ-NMMs formula was loaded into Eudragit S100-coated capsules where in vitro release and in vivo X-ray imaging ensured protection of ITZ release in either the stomach or intestine and targeting it to the colon. Such results suggested promising ITZ-NMMs system, capable of enhancing ITZ solubility in the intended target site, therefore, can be used not only in the treatment of colon fungal infections but also augments colon cancer therapy.

Factors Associated with Outcome in Patients Managed for Invasive Fungal Infections at the Infectious Diseases Department of a Tertiary Care Hospital

Objective: To look for the factors associated with outcomes in patients managed for invasive fungal infections at the Infectious Diseases Department of a Tertiary Care Hospital
 Study Design: Comparative cross-sectional study
 Place and Duration of Study: Department of Infectious Diseases, Pak Emirates Military Hospital, Rawalpindi Pakistan,from Apr 2021 to Sep 2022.
 Methodology: A total of 90 patients with a different types of invasive fungal infections diagnosed by consultant infectious diseases were recruited. First, they were given standard treatment for fungal infection; they were diagnosed as per guidelines.Then, they were followed up for one month to look for an outcome. 
 Results: Out of 90 patients with invasive fungal infections included in the study, 62(68.8%) had a good outcome, while 28(31.2%) had a poor outcome. The mean age of the patients recruited in our study was 39.54±6.27 years. Of all the participants, 65(72.2%) patients were male, while 25(27.8%) were female. Statistical analysis revealed that poorly controlled diabetes, COVID-19 infection and HIV positive were statistically significantly associated with poor outcomes in our study participants (p-value<0.05).
 Conclusion: The Considerable number of patients with invasive fungal infections had a poor outcome in our study. The presence of poorly controlled diabetes, COVID-19 infection and being HIV positive were the factors associated with poor outcomes in our study participants.

Antifungal Compounds from Microbial Symbionts Associated with Aquatic Animals and Cellular Targets: A Review.

Fungal infections continue to be a serious public health problem, leading to an estimated 1.6 million deaths annually. It remains a major cause of mortality for people with a weak or affected immune system, such as those suffering from cancer under aggressive chemotherapies. On the other hand, pathogenic fungi are counted among the most destructive factors affecting crops, causing a third of all food crop losses annually and critically affecting the worldwide economy and food security. However, the limited number currently available and the cytotoxicity of the conventional antifungal drugs, which are not yet properly diversified in terms of mode of action, in addition to resistance phenomena, make the search for new antifungals imperative to improve both human health and food protection. Symbiosis has been a crucial alternative for drug discovery, through which many antimicrobials have been discovered. This review highlights some antifungal models of a defensive symbiosis of microbial symbiont natural products derived from interacting with aquatic animals as one of the best opportunities. Some recorded compounds with supposed novel cell targets such as apoptosis could lead to the development of a multitherapy involving the mutual treatment of fungal infections and other metabolic diseases involving apoptosis in their pathogenesis pathways.

Succinylation modification provides new insights for the treatment of immunocompromised individuals with drug-resistant Aspergillus fumigatus infection.

Invasive Aspergillus fumigatus infection poses a serious threat to global human health, especially to immunocompromised individuals. Currently, triazole drugs are the most commonly used antifungals for aspergillosis. However, owing to the emergence of drug-resistant strains, the effect of triazole drugs is greatly restricted, resulting in a mortality rate as high as 80%. Succinylation, a novel post-translational modification, is attracting increasing interest, although its biological function in triazole resistance remains unclear. In this study, we initiated the screening of lysine succinylation in A. fumigatus. We discovered that some of the succinylation sites differed significantly among strains with unequal itraconazole (ITR) resistance. Bioinformatics analysis showed that the succinylated proteins are involved in a broad range of cellular functions with diverse subcellular localizations, the most notable of which is cell metabolism. Further antifungal sensitivity tests confirmed the synergistic fungicidal effects of dessuccinylase inhibitor nicotinamide (NAM) on ITR-resistant A. fumigatus. In vivo experiments revealed that treatment with NAM alone or in combination with ITR significantly increased the survival of neutropenic mice infected with A. fumigatus. In vitro experiments showed that NAM enhanced the killing effect of THP-1 macrophages on A. fumigatus conidia. Our results suggest that lysine succinylation plays an indispensable role in ITR resistance of A. fumigatus. Dessuccinylase inhibitor NAM alone or in combination with ITR exerted good effects against A. fumigatus infection in terms of synergistic fungicidal effect and enhancing macrophage killing effect. These results provide mechanistic insights that will aid in the treatment of ITR-resistant fungal infections.

Rising burden of superficial fungal infections in India and the role of Clotrimazole for optimal management

Cutaneous dermatophytosis are among the most common infections seen in clinical practice. Over the past few years there has been a rising trend in the prevalence with change in spectrum of infection and isolation of some uncommon species. Recognition and appropriate treatment of these infections is important to reduce the morbidity and discomfort and also reduce the possibility of transmission. Azoles are the antifungal agents used extensively to treat dermatophytosis. Clotrimazole is mainly used locally in the treatment of skin fungal infections due to dermatophytes and yeasts. It is known to provide a broad-spectrum antifungal coverage against dermatophytes, moulds, yeasts and some bacteria, and is an efficient, safe and well accepted treatment for skin fungal infections in children and adults. This review provides an overview of the role of topical clotrimazole available as cream and powder and in combination with topical steroid for the optimal management of skin fungal infections.