Academic literature on the topic 'Anti-fungals'

The design and synthesis of new, safe and potent molecules to apply against soil-borne pathogens is a critical goal for organic and bio-medicinal chemists. Herein, we designed and synthesized a series of benzimidazole-based carbamate derivatives (7a–f), as soil-borne anti-fungals. The derivatives 7a–f were all synthesized in multi-step reactions with acceptable yields. The structures of 7a–f were all identified and characterized using 1H-NMR, IR, HRMS, and melting point calculations. The final compounds were tested on five soil-borne pathogens. The results of various bio-assays showed that compounds 7a-3, 7a-2, 7b-2, 7a-1 and 7b-1 significantly affected the growth of Pythium aphanidermatum, a serious pathogen affecting vegetable crops worldwide. Compounds 7a-1 and 7b-1 were the most efficacious, which resulted in a 96% growth inhibition in Pythium at 100 mg L−1. In conclusion, we reported the potent carbamate derivatives as soil-borne anti-fungals, and believe that the synthesis of more derivatives related to the current scaffold would be beneficial.

The inappropriate use of antifungals is associated with greater antimicrobial resistance, costs, adverse events, and worse clinical outcomes. The aim of this study was to determine prescription patterns and approved and unapproved indications for systemic antifungals in a group of patients in Colombia. This was a cross-sectional study on indications for the use of systemic antifungals in outpatients from a drug dispensing database of approximately 9.2 million people affiliated with the Colombian Health System. Sociodemographic, pharmacological, and clinical variables were considered. Descriptive, bivariate, and multivariate analyses were performed. A total of 74,603 patients with antifungal prescriptions were identified; they had a median age of 36.0 years (interquartile range: 22.0–53.0 years), and 67.3% of patients were women. Fluconazole (66.5%) was the most prescribed antifungal for indications such as vaginitis, vulvitis, and vulvovaginitis (35.0%). A total of 29.3% of the prescriptions were used in unapproved indications. A total of 96.3% of ketoconazole users used the medication in unapproved indications. Men (OR: 1.91; CI95%: 1.79–2.04), <18 years of age (OR: 1.20; CI95%: 1.11–1.31), from the Caribbean region (OR: 1.26; CI95%: 1.18–1.34), with chronic obstructive pulmonary disease (OR: 1.80; CI95%: 1.27–2.54), prescriptions made by a general practitioner (OR: 1.17; CI95%: 1.04–1.31), receiving comedications (OR: 1.58; CI95%: 1.48–1.69), and the concomitant use of other antimicrobials (OR: 1.77; CI95%: 1.66–1.88) were associated with a higher probability that the antifungal was used for unapproved indications; deep mycosis (OR: 0.49; CI95%: 0.41–0.58), prescribing fluconazole (OR: 0.06; CI95%: 0.06–0.06), and having diabetes mellitus (OR: 0.33; CI95%: 0.29–0.37), cancer (OR: 0.13; CI95%: 0.11–0.16), or HIV (OR: 0.07; CI95%: 0.04–0.09) reduced this risk. Systemic antifungals were mostly used for the management of superficial mycoses, especially at the gynecological level. In addition, more than a quarter of patients received these medications in unapproved indications, and there was broad inappropriate use of ketoconazole.

The purpose of this article is to review and update the strategies for prevention and treatment of invasive aspergillosis (IA) in pediatric patients with leukemia and in patients with hematopoietic stem cell transplantation. The major risk factors associated with IA will be described since their recognition constitutes the first step of prevention. The latter is further analyzed into chemoprophylaxis and non-pharmacologic approaches. Triazoles are the mainstay of anti-fungal prophylaxis while the other measures revolve around reducing exposure to mold spores. Three levels of treatment have been identified: (a) empiric, (b) pre-emptive, and (c) targeted treatment. Empiric is initiated in febrile neutropenic patients and uses mainly caspofungin and liposomal amphotericin B (LAMB). Pre-emptive is a diagnostic driven approach attempting to reduce unnecessary use of anti-fungals. Treatment targeted at proven or probable IA is age-dependent, with voriconazole and LAMB being the cornerstones in >2yrs and <2yrs age groups, respectively.

Being eukaryotes the similarity of fungi with animals in great extent, it is very difficult to develop suitable antifungal compounds which target only to the fungi and spare the host compare to anti-bacterials. Concerted systematic programmes to discover and develop new antibiotics and anti-fungals have been driven to a considerable extent by the development of resistance by these organisms to the drugs commonly used against them as well as the side effects they exerted on host body. Fungal diseases are usually divided into five groups according to the level of infected tissue and mode of entry into the host which are: superficial, cutaneous, subcutaneous, systemic, and opportunistic infections. The most common types of mycoses which are responsible for humans fungal diseases are- Tinea capitis; disease of Scalp (Trichophyton spp. and Microsporum spp.), Tinea corporis: Due to social exchanges and contacts (Trichophyton spp.), Tinea cruris: Disease of itching (Epidermophyton sp.), Tinea pedis: Athletes foot, in bengali 'haza' (T. rubrum), Tinea manuum: similar disease on hands (T. rubrum), and Tinea unguium: Attacking nails (T. rubrum).

Multi drug resistant Mycobacterial and invasive fungal infections imposes immense Global health burden resulting in high morbidity and mortality rates. The biggest delima is the time consuming culture and sensitivity diagnostics i.e 04 to 06 weeks for Mycobacterial and 02 to 04 weeks for fungal infections. The delay in result provision adds up to patient’s miseries especially for resistant cases. Therefore the aim of writing this short commentary was to introduce multiplex PCR via microarray bead hybridization assay. A thorough literature review was found extremely deficient. However, a limited published data concluded this technique as a surrogate for rapid molecular and resistant gene depiction for mycobacterial and fungal species directly from clinical specimens. Another biggest advantage was simultaneous genomics and resistant genes identification for Mycobacterial and Fungal isolates. The resistant genes for 1st line anti tuberculous therapy (ATT), 2nd line ATT and commonly used anti fungals can be detected easily. This cost effective test can be finalized in approximately less than 24 hours. Thus early and accurate management can be timely started for both said infections.

Histatins constitute a group of small, cationic multifunctional proteins present in the saliva of human and some nonhuman primates. The most significant function of histatins may be their anti-fungal activity against Candida albicans and Cryptococcus neoformans. Histatins have been extensively studied at both the protein and gene levels. The structure-function relationship of histatins with respect to their candidacidal activity has also been studied by means of recombinant histatin variants, as well as by chemically synthesized histatin fragments. The mechanism of histatins' action on Candida albicans is not clear, but it appears to be different from that of azole-based anti-fungal drugs which interrupt ergosterol synthesis. During the past 20 years, fungal infections have become more prevalent as a result of the emergence of AIDS, as well as, paradoxically, modern medical advances. The toxicity of current anti-fungal medicine, the emergence of drug-resistant strains, and the availability of only a few types of anti-fungal agents are the major disadvantages of current anti-fungal therapy. Therefore, the importance of the search for new, broad-spectrum anti-fungals with little or no toxicity cannot be overemphasized. The following properties make histatins promising anti-fungal therapeutic agents: (1) They have little or no toxicity; (2) they possess high cidal activities against azole-resistant fungal species and most of the fungal species tested; and (3) their candidacidal activity is similar to that of azole-based antifungals. Current research efforts focus on the development of improved histatins with enhanced cidal activity and stability, and of suitable and effective histatin delivery systems. These and other approaches may help to outpace the growing list of drug-resistant and opportunistic fungi causing life-threatening, disseminating diseases. The histatins with improved protective properties may also be used as components of artificial saliva for patients with salivary dysfunction.

Background: Pachyonychia congenita (PC) comprises a group of rare autosomal dominant genetic disorders. It is characterized by hypertrophic nail dystrophy, focal palmoplantar keratoderma, follicular keratosis, and oral leukokeratosis. It is associated with mutations in five differentiationspecific keratin genes: KRT6A, KRT6B, KRT6C, KRT16, or KRT17. The case is being reported for its rarity. To the best of our knowledge, this is the first report of PC, from Vietnam, confirmed by genetic analysis. Case presentation: A four-year-old Vietnamese girl presented with a thickened nail and oral leukokeratosis soon after birth. She was diagnosed with onychomycosis and chronic oral candidiasis and was treated with systemic anti-fungals in children's hospitals and dermatology departments multiple times; however, no treatments were effective. In collaboration with the International Pachyonychia Congenita Research Registry (IPCRR), the clinical features were consistent with a diagnosis of PC type PC-K6a. The genetic testing, performed through the IPCRR, shows a K6a N171K mutation. Conclusions: The IPCRR helps screen PC's clinical features and confirm a diagnosis at the molecular level, which is beneficial and crucial for validating the condition's clinical impression.

This study has involved the analysis of volatile fingerprints using a hybrid electronic nose (e-nose) to discriminate between and diagnose the microorganisms which cause ventilator–associated pneumonia (VAP), one of the most important infections in the hospital environment. This infection occurs in hospitalised patients with 48-72 hrs of mechanical ventilation. VAP diagnostics still remains a problem due to the lack of a precise diagnostic tool. The current tests are mostly based on quantitative cultures of samples from the lower lung airways with clinical findings, which do not often result in accurate diagnoses of the disease. Cont/d.

Pathogenic fungi are responsible for causing significant disease in both humans and plants. Fungal infections are responsible for 1.5 million deaths annually, and despite the availability of antifungal treatments, mortality rates remain high. Fungi not only cause human disease, but can also infect plants, crops and fruits, thereby, being a major threat for secure food production and the economy. Fungi are developing resistance to the few classes of antifungals that are available to treat human or agricultural infections. Hence, novel antifungal agents are required. Biotin is an essential co-factor required for all forms of life. It is covalently attached to biotin-dependent enzymes and participates in the metabolic reactions these enzymes perform. The enzyme responsible for the ATP-dependent attachment of biotin onto these enzymes is biotin protein ligase (BPL), which attaches biotin onto a conserved lysine residue in the biotin domain of the biotin-dependent enzymes. BPL is essential for the viability of bacteria and fungi, therefore, it is proposed as a promising target for the development of novel anti-infectives. Whilst inhibitors against the BPLs from Staphylococcus aureus and Mycobacterium tuberculosis have been reported, BPL has not been targeted for the development of novel antifungals. This thesis investigates the BPLs from the model fungi Saccharomyces cerevisiae and from two pathogenic fungi responsible for causing agricultural disease. Fungal BPLs are structurally unique compared to bacterial homologs as they contain an additional N-terminal extension prior to the common catalytic domain and C-terminal cap found in all BPLs. BPLs with this extension are termed class III BPLs. Currently there is no atomic resolution structure of a class III enzyme and the function of the additional N-terminal extension is unknown. This thesis investigates the structure of these class III enzymes. The BPLs from Saccharomyces cerevisiae, Botrytis cinerea and Zymoseptoria tritici were characterised for their potential as antifungal drug targets. These three enzymes had similar overall structures as expected from their sequence homology. However, they displayed different stabilities and variable Michaelis constants for the substrates biotin, MgATP and the biotin domain, which implied subtle structural differences between the enzymes. These class III BPLs varied in their preferences for different species’ biotin domains, providing further evidence for a ‘substrate selectivity verification’ mechanism whereby the N-terminal extension of class III BPLs is proposed to distinguish between substrates and select only those appropriate for biotinylation. Finally, potent and selective in vitro inhibition of these class III BPLs was demonstrated using chemical analogs of the reaction intermediate, supporting the hypothesis that fungal BPLs are druggable antifungal targets. The structure of the S. cerevisiae BPL (ScBPL) was investigated in greater detail, and structural changes that occur upon ligand binding were examined. Whilst gross structural changes did not occur concomitant with ligand binding, smaller structural changes including rigidification and a reduction in the dynamic movement of the enzyme occurred such that ScBPL stability increased. Homology modelling and hydrogen-deuterium exchange (HDX) mass spectrometry revealed a structured domain present in the N-terminal extension, with a predicted fold homologous to a glutamine amidotransferase. This N-terminal domain was linked to the structurally conserved BPL catalytic domain by a 160-residue linker that was mostly folded and/or buried. Together, HDX and homology modelling revealed that ligand binding induced local structural rearrangements in the N-terminal domain and the ligand-binding site of the catalytic domain. Finally, HDX also identified potential interaction surfaces of each domain indicating intramolecular interactions that govern BPL function. Overall, this project aims to understand the structure of a class III BPL in order to target these enzymes for the development of novel antifungal agents for the treatment of both agricultural and clinical infections.
Thesis (Ph.D.) -- University of Adelaide, School of Biological Sciences, 2020