Subject: Medicine & Pharmacology, Allergology Keywords: antimicrobial resistance; antimicrobial stewardship; antiviral resistance; antibacterial resistance; antimalarial resistance; antifungal resistance; One Health; Uganda
Online: 14 April 2021 (12:57:40 CEST)
The global burden of antimicrobial resistance is on the rise, resulting in higher morbidity and mortality in our communities. The spread of antimicrobial resistance in the environment and development of resistant microbes is a challenge to the control of antimicrobial resistance. Approaches, such as antimicrobial stewardship programmes, and enhanced surveillance, have been devised to curb its spread. However, particularly in lower- and middle-income countries, the overall extent of antimicrobial resistance, and knowledge on on-going surveillance, stewardship or investigation efforts, re often poorly understood. This study aimed to look at the efforts that have been undertaken to combat antimicrobial resistance in Uganda as a means of establishing an overview of the situation, to help inform future decisions. We conducted a systematic literature review of the PubMed database to assess the efforts that have been done in Uganda to investigate and combat antimicrobial resistance. A search combining keywords associated with antimicrobial resistance were used to look up relevant studies between 1995 and 2020 on surveillance of antimicrobial resistance in Uganda, and susceptibility of microbes to different drugs. The search yielded 430 records, 163 of which met the inclusion criteria for analysis. The studies were categorized according to country and region, the type of antimicrobial resistance, context of the study, study design and outcome of the study. Antibacterial resistance and antimalarial resistance had the most published studies while antiviral and antifungal resistance each were represented by very few studies. Most studies were conducted in humans and hospital settings, with very few in veterinary and One Health contexts. The results from our work can inform public health policy on antimicrobial stewardship as it contributes to understanding the status of antimicrobial resistance surveillance in Uganda, and can also help to guide future research efforts. Notably, a One Health approach needs to be followed with re-spect to surveillance of antimicrobial resistance to better understand the mechanisms of resistance transfer across the human-animal–environment interface, including additional investigation in antiviral and antifungal resistance.
REVIEW | doi:10.20944/preprints202102.0405.v1
Subject: Keywords: drug repurposing; antifungal therapy; antifungal mechanism; clinical application; antifungal agents
Online: 18 February 2021 (10:21:38 CET)
The morbidity and mortality caused by invasive fungal infections is increasing across the globe due to developments in transplant surgery, the use of immunosuppressive agents, and the emergence of drug-resistant fungal strains, which has led to a challenge in terms of treatment due to the limitations of three classes of drugs. Hence, it is imperative to establish effective strategies to identify and design new antifungal drugs. Drug repurposing is an effective way of expanding the application of existing drugs. In the last years, various existing drugs have been shown to be useful in the prevention and treatment of the invasive fungi. In this review, we summarize the currently used antifungal agents. In addition, the most up to date information on the effectiveness of existing drugs with antifungal activity is discussed. Moreover, the antifungal mechanisms of existing drugs are highlighted. These data will provide valuable knowledge to stimulate further investigation and clinical application in this field.
REVIEW | doi:10.20944/preprints202103.0717.v1
Subject: Life Sciences, Biochemistry Keywords: virulence; antifungal resistance; non-canonical RNAi; epimutant; R3B2; RdRP; transposon; genome stability; Mucorales; mucormycosis.
Online: 30 March 2021 (09:37:39 CEST)
Mucorales are the causal agents for the lethal disease known as mucormycosis. Mortality rates of mucormycosis can reach up to 90%, due to the mucoralean antifungal drug resistance and the lack of effective therapies. A concerning urgency among the medical and scientific community claims to find targets for the development of new treatments. Here, we reviewed different studies de-scribing the role and machinery of a novel non-canonical RNAi pathway (NCRIP) only conserved in Mucorales. Its non-canonical features are the independence of Dicer and Argonautes proteins. Conversely, NCRIP relies on RNA-dependent RNA Polymerases and an atypical ribonuclease III (RNaseIII). NCRIP regulates the expression of mRNAs by degrading them in a specific manner. Its mechanism binds dsRNA but only cuts ssRNA. NCRIP exhibits a diversity of functional roles. It represses the epimutational pathway and the lack of NCRIP increases the generation of drug resistant strains. NCRIP also regulates the control of retrotransposons expression, playing an essential role in genome stability. Finally, NCRIP regulates the response during phagocytosis, affecting the multifactorial process of virulence. These critical NCRIP roles in virulence and antifungal drug resistance, along with its exclusive presence in Mucorales, mark this pathway as a promising target to fight against mucormycosis.
ARTICLE | doi:10.20944/preprints202011.0149.v1
Subject: Materials Science, Biomaterials Keywords: turmeric; neem; antibacterial; antifungal; polyethylene
Online: 3 November 2020 (13:58:22 CET)
With the increased scientific interest in green technologies, many researches have been focused on the production of polymeric composites containing naturally occurring reinforcing particles. Apart from increasing mechanical properties, these additions can have a wide range of interesting effects, such as increasing the resistance to bacterial and fungal colonization. In this work, different amounts of two different natural products, namely neem and turmeric, have been added to polyethylene to act as a natural antibacterial and antifungal product for food packaging applications. Microscopic and spectroscopic characterization showed that fractions up to 5% of these products can be dispersed into low-molecular weight polyethylene, while higher amounts could not be properly dispersed and resulted in an inhomogeneous, fragile composite. In vitro testing conducted with Escherichia coli, Staphylococcus aureus and Candida albicans showed a reduced proliferation of pathogens when compared to the polyethylene references. In particular, turmeric, resulted to be more effective against E. coli when compared to neem, while they had similar performances against S. aureus. Against C. albicans, only neem was able to show a good antifungal behavior, at high concentrations. Tensile testing showed that the addition of reinforcing particles reduces the mechanical properties of polyethylene, and, in the case of turmeric, it is further reduced by UV irradiation.
REVIEW | doi:10.20944/preprints202105.0554.v1
Online: 24 May 2021 (10:24:20 CEST)
Therapeutic Drug Monitoring (TDM) is potentially a useful tool that can be employed to increase the efficacy and decrease the toxicity of antifungal drugs. The aim of this narrative review is to provide an overview of the current use of TDM in clinical practice, and to present the evidence available regarding its use in proactive clinical settings for preventing and managing treatment failure. This review also presents the existing evidence regarding the association of various clinical outcomes with specific thresholds of drug concentrations in everyday practice. Articles concerning the use of TDM of triazoles in the treatment of fungal infections were retrieved through an electronic search using PubMed. In clinical practice, TDM has an increasingly important role in the management of antifungal drugs as a consequence of the improvement in the knowledge of the pharmacokinetics and pharmacodynamics of these drugs. The currently available evidence shows a direct exposure-response relationship for triazoles, though the PK/PD profile is unpredictable. Current guidelines and treatment consensus statements recommend the proactive TDM of voriconazole, posaconazole, and itraconazole to optimize dosage regimens and improve outcomes for adult and pediatric patients.
ARTICLE | doi:10.20944/preprints202012.0182.v1
Subject: Medicine & Pharmacology, Allergology Keywords: candida; bloodstream infection; pediatric; neonatal; antifungal
Online: 8 December 2020 (07:47:24 CET)
Background. Candida bloodstream infections (CBSIs) have decreased among pediatric populations in the United States, but remain an important cause of morbidity and mortality. Species distributions and susceptibility patterns of CBSI isolates diverge widely between children and adults. Awareness of these patterns can inform clinical decision-making for empiric or pre-emptive therapy of children at risk for candidemia. Methods. CBSIs occurring from 2006-2016 among patients in a large children’s hospital were analyzed for age specific trends in incidence rate, risk factors for breakthrough-CBSI and death, as well as underlying conditions. Candida species distributions and susceptibility patterns were evaluated in addition to antifungal agent use. Results. The overall incidence rate of CBSI among this complex patient population was 1.97/1,000 patient-days. About half of CBSI episodes occurred in immunocompetent children and 14% in Neonatal Intensive Care Unit (NICU) patients. Antifungal resistance was minimal: 96.7% of isolates were fluconazole-, 99% were micafungin-, and all were amphotericin susceptible. Liposomal amphotericin was the most commonly prescribed antifungal agent including for NICU patients. Overall CBSI-associated mortality was 13.7%; there were no deaths associated with CBSI among NICU patients after 2011. Conclusions. Pediatric CBSI characteristics differ substantially from those in adults. Improved management of underlying diseases and antimicrobial stewardship may further decrease morbidity and mortality from CBSI while continuing to maintain low resistance rates among Candida isolates.
REVIEW | doi:10.20944/preprints201911.0392.v1
Subject: Chemistry, Medicinal Chemistry Keywords: fungal pathogens; antifungal agents; natural products
Online: 30 November 2019 (11:30:19 CET)
In this review, we discuss novel natural products discovered within the last decade that are reported to have antifungal activity against pathogenic species. Nearly a hundred natural products were identified that originate from bacteria, alga, fungi, sponges and plants. Fungi were the most prolific source of antifungal compounds discovered during the period of review. The structural diversity of these antifungal leads encompasses all the major classes of natural products including polyketides, shikimate metabolites, terpenoids, alkaloids and peptides.
REVIEW | doi:10.20944/preprints201610.0049.v1
Subject: Biology, Agricultural Sciences & Agronomy Keywords: plant extracts; antifungal activity; fungal pathogens
Online: 13 October 2016 (11:50:21 CEST)
Abstract Plant fungal pathogens are frequently found as one of limiting factors for crop production. More than 10,000 species of fungi can cause disease in plants. To control the diseases, many farmers are still rely on the use of chemical fungicides, however most synthetic fungicides can cause acute toxicity, and some cause chronic toxicity as well. Thus, an appropriate technological improvement towards a more effective use of natural resources is required in agriculture to develop environmentally friendly sustainable farming system. This paper highlights the potential of extracts of tropical plants as antifungal agent to control plant fungal diseases. Information and data presented in this paper are mainly derived from selected and related references that previously published in the scientific journals. Many higher plants of tropical origin with fungicidal activities and their potential for fungal disease control of agricultural crops have been studied, however most of the studies have been done under in vitro condition. Some plant extracts showed strong antifungal activities on in vitro as well as in vivo tests, but some plant extracts showed significant antifungal activities on in vitro test, but did not obvious on in vivo tests. A great variation in antifungal activities were shown by plants extracts of different species and plant parts, in one hand, and on the other hand, variation was also observed on the responses of different fungal species to the same plant extract. Since the purpose of the use of plant extract is to control plant fungal diseases, the field trial is needed to ensure the stability of efficacy of certain plant extract. In addition, isolation and identification of active substances in the extracts is needed to assess possible mode of action and side effect of their use.
REVIEW | doi:10.20944/preprints202108.0276.v1
Subject: Life Sciences, Other Keywords: dermatophytes; antifungals; antifungal susceptibility testing; drug combination
Online: 12 August 2021 (13:16:42 CEST)
Dermatophytes are the most common cause of fungal infections worldwide, affecting millions of people annually. The emergence of resistance among dermatophytes along with the availability of antifungal susceptibility procedures suitable for testing antifungal agents against this group of fungi make the combinatorial approach particularly interesting to be investigated. Therefore, we reviewed the scientific literature concerning the antifungal combinations in dermatophytes. A literature search on the subject performed in PubMed yielded 68 publications: 37 articles referring to in vitro studies, and 31 articles referring to case reports/clinical studies. In vitro studies involved over 400 clinical isolates of dermatophytes (69% Trichophyton spp., 29% Microsporum spp., and 2% Epidermophyton floccosum). Combinations included two antifungal agents or an antifungal agent plus another chemical compound including plant extracts/essential oils, calcineurin inhibitors, peptides, disinfectant agents and others. In general, drug combinations yielded variable results spanning from synergism to indifference. Antagonism was rarely seen. In over 700 patients with documented dermatophyte infections an antifungal combination approach could be evaluated. The most frequent combination included a systemic antifungal agent administered orally (i.e.: azole [mainly itraconazole], terbinafine or griseofulvin) plus a topical medication (i.e.: azole, terbinafine, ciclopirox, amorolfine) for several weeks. Clinical results indicate that association of antifungal agents is effective, and it might be useful in accelerate the clinical and microbiological healing of a superficial infection. Antifungal combinations in dermatophytes have gained considerable scientific interest over the years and, in consideration of the interesting results available as far, it is desirable to continue the research in this field.
ARTICLE | doi:10.20944/preprints201903.0113.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: biosurfactant; Rhodotorula glutinis; antifungal activity; saprophytic fungi
Online: 11 March 2019 (07:50:52 CET)
Background: Biosurfactants are amphiphilic surface active compounds that produced by several microorganisms, including, bacteria and fungi. Biodegradability, low toxicity, applications diversity and functionality under extreme conditions are characterized them from chemically biosurfactants. It is found that, Rhodotorula species, read yeasts, have high potency for biosurfactant producing. Recently, antimicrobial activities of biosurfactants have been subjected for new antibiotic therapy. The aim of the present study was to evaluate biosurfactant production by the different strains of Rhodotorula species in laboratory conditions. In addition, antifungal activity of produced biosurfactant was assessed against several saprophytic fungi. In the present study 54 strains of Rhodotorula including, R. glutinis (48 strains), R. minuta (2 strains), R. mucilaginosa (2 strains) and Rhodotorula species (2 strains) were screened for biosurfactant production. The biosurfactant was produced using the Sabouraud dextrose broth medium and confirmed by specific tests. Antifungal assay was also evaluated by disk diffusion method and the serial dilutions of biosurfactant. In the present study, although all tested strains were capable to produce biosurfactant in vitro, the degree of biosurfactant production was varied among stains. 7.4% strains had the highest (+5) biosurfactant activity followed by 16.7%, 29.5%, 25.8% and 20.4% had +4, +3, +2 and +1, respectively. In the present study, all tested fungi were inhibited at 40 µl of biosurfactant. Rhodotorula species are appropriate organisms for the production of biosurfactants and R. glutinis strains have the greatest ability to producing biosurfactant than another species. Furthermore, our results were demonstrated that the produced biosurfactant by R. glutinis presented a valuable potential for biopharmaceutical applications.
ARTICLE | doi:10.20944/preprints202012.0407.v1
Subject: Biology, Anatomy & Morphology Keywords: Endophyte; Aspergillus ochraceus; antifungal; neoaspergillic acid; ixodicidal; mellein
Online: 16 December 2020 (12:18:34 CET)
In the current study, an ethyl acetate extract from the endophytic fungus Aspergillus ochraceus SPH2 isolated from the stem parts of the endemic plant Bethencourtia palmensis was screened for its biocontrol properties against plant pathogens (Fusarium moniliforme, Alternaria alternata and Botrytis cinerea), insect pests (Spodoptera littoralis, Myzus persicae, Rhopalosiphum padi), plant parasites (Meloidogyne javanica) and ticks (Hyalomma lusitanicum). SPH2 gave extracts with strong fungicidal and ixodicidal effects at different fermentation times. The bioguided isolation of these extracts gave compounds 1-3. Mellein (1) showed strong ixodicidal effects and was also fungicidal. This is the first report on the ixodicidal effects of 1. Neoaspergillic acid (2) showed potent antifungal effects. Compound 2 appeared during the exponential phase of the fungal growth while neohydroxyaspergillic acid (3) appeared during the stationary phase, suggesting that 2 is the biosynthetic precursor of 3. Additional molecular ions compatible with pyrazynes that were detected during the exponential phase included flavacol, and aspergilliamide while ochramide A was mostly detected during the stationary phase of the fermentation. Moreover, polyketids were also detected during the sationaty phase of the fermentation curve (dihydroaspyrone, aspyrone, asperlactone) and the alkaloid circumdatin H. Ochratoxin A was not detected. Therefore, SPH2 could be a potential biotechnological tool for the production of ixodicidal mellein.
ARTICLE | doi:10.20944/preprints201901.0216.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: Phloroglucide, Polyhydroxyl aromatic compounds, SiO2-BTSA, Antifungal, Antibacterial.
Online: 22 January 2019 (11:30:45 CET)
An efficient procedure for the synthesis of polyhydroxyl aromatic compounds (phloroglucide analogs) is described. In this procedure a reaction was done between different 4-substituted phenols and 2,6-bis(hydroxymethy) phenols. The reactions proceed in the presence of catalytic amount of silica gel supported boric tri-sulfuric anhydride (SiO2-BTSA) in excellent yields. 16 compounds were synthesized (I1-I16). Chemical structures of all compounds were confirmed by spectroscopic methods. We optimized the chemical reactions in the presence of different acidic catalysts, different solvents and also different temperatures. Catalytic amounts of SiO2-BTSA in dichloroethane (DCE) was the best conditions. Some of the synthesized compounds were screened for their antimicrobial activities. Antifungal and antibacterial activities of the synthesized compounds were evaluated by broth micro dilution method as recommended by CLSI. Some of the tested compounds show good in vitro biological properties.
ARTICLE | doi:10.20944/preprints202212.0467.v1
Subject: Life Sciences, Microbiology Keywords: azole drugs; cryptococcal meningitis; resistance; synergism; synthetic antifungal peptides
Online: 26 December 2022 (03:44:06 CET)
Cryptococcus neoformans is a multidrug-resistant human pathogenic yeast responsible for infections in immunocompromised patients. Here, Itraconazole (ITR), a commercial antifungal drug with low effectiveness against C. neoformans, was combined with different synthetic peptides Mo-CBP3-PepII, RcAlb-PepII, RcAlb-PepIII, PepGAT, and PepKAA. The mechanisms of action responsible for the synergistic effect were evaluated for the best combinations by Fluorescence Microscopy (FM). The synthetic peptides enhanced the activity of ITR by 10-fold against C. neoformans. Our results demonstrated that the combinations could induce pore formation in the membrane and overaccumulation of ROS on C. neoformans cells. Our findings indicate that our peptides successfully potentialize the activity of ITR by reducing it by 10-fold to reach antifungal activity against C. neoformans. Therefore, synthetic peptides are potential molecules to act as co-adjuvant agents in treating Cryptococcal infections.
ARTICLE | doi:10.20944/preprints202210.0063.v1
Subject: Chemistry, Organic Chemistry Keywords: Antifungal activities; synthesis; indole Schiff base derivatives; 1,3,4-thiadiazole
Online: 6 October 2022 (10:27:10 CEST)
A series of novel indole Schiff base derivatives (2a–2t) containing a 1,3,4-thiadiazole scaffold modified with a thioether group were synthesized, and their structures were confirmed using FT-IR, 1H NMR, 13C NMR, andHR-MS. In addition, the antifungal activity of synthesized indole derivatives was investigated against Fusarium graminearum (F. graminearum), Fusarium oxysporum (F. oxysporum), Fusarium moniliforme (F. moniliforme), Curvularia lunata (C. lunata), and Phytophthora parasitica var. nicotiana (P. p. var. nicotianae) using the mycelium growth rate method. Among the synthesized indole derivatives, compound 2j showed the highest inhibition rates of 100%, 95.7%, 89%, and 76.5% at a concentration of 500 μg/mL against F. graminearum, F. oxysporum, F. moniliforme, and P. p. var. nicotianae, respectively. Similarly, compounds 2j and 2q exhibited higher inhibition rates of 81.9% and 83.7% at a concentration of 500 μg/mL against C. lunata. In addition, compound 2j has been recognized as a potential compound for further investigation in the field of fungicides.
ARTICLE | doi:10.20944/preprints202108.0424.v1
Subject: Chemistry, Medicinal Chemistry Keywords: hydrazone; Candida species; antifungal agents; Candida albicans; Candida glabrata
Online: 23 August 2021 (10:29:47 CEST)
The treatment of benzylidenemalononitriles 3a-c with phenylhydrazines 4a-n in refluxing ethanol did not provide pyrazole derivatives but furnished hydrazones 1a-o. The structure of hydrazones was secured by X-Ray analysis. Newly synthesized hydrazones 1a-o were tested against 8 Candida spp. strains in a dose response assay to determine the minimum inhibitory concentration (MIC99). Five compounds 1c, 1d, 1i, 1k and 1l were identified as promising antifungal agents against Candida spp. (C. albicans SC5314, C. glabrata, C. tropicalis, C. parapsilosis and C. glabrata (R azoles)) with MIC99 values ranging from 16 to 32 µg/mL. To further evaluate the antifungal potential of the active compounds, they have been assayed against a mammalian cell line HEK293 to determine general cell toxicity and on NCI-60 cancer cell lines panel, demonstrating selectivity antifungal activity over cytotoxicity.
REVIEW | doi:10.20944/preprints202106.0575.v1
Subject: Life Sciences, Biochemistry Keywords: Candida glabrata; candidiasis; virulence factors; biofilm; antifungal drug resistance
Online: 23 June 2021 (11:21:53 CEST)
Candida glabrata is a yeast of increasing medical relevance, particularly in critically ill patients. It is the second most isolated Candida species associated with invasive candidiasis (IC) behind C. albicans. The attributed higher incidence is primarily due to an increase in the acquired immunodeficiency syndrome (AIDS) population, cancer, and diabetes patients. The elderly population and the frequent use of indwelling medical devices are also predisposing factors. The work aimed to review various virulence factors that facilitate the survival of pathogenic C. glabrata in IC. The available published research articles related to the pathogenicity of C. glabrata were retrieved and reviewed from four credible databases, mainly Google Scholar, ScienceDirect, PubMed, and Scopus. The articles highlighted many virulence factors associated with pathogenicity in C. glabrata, including adherence to a susceptible host surface, evading host defences, and producing hydrolytic enzymes (e.g., phospholipases, proteases, and haemolysins). The factors facilitate infection initiation. Other virulent factors include iron regulation and genetic mutations. Accordingly, biofilm production, tolerance to high-stress environments, and development of resistance to the antifungal drug, notably to fluconazole and other azole derivatives, were reported. The review provided evident pathogenic mechanisms and antifungal resistance associated with C. glabrata in ensuring its sustenance and survival.
ARTICLE | doi:10.20944/preprints201707.0093.v1
Subject: Keywords: triiodide; antibacterial activity; antifungal activity; sodium; crown ether complex
Online: 31 July 2017 (15:25:01 CEST)
New antibacterial agents are needed to overcome the increasing number of infectious diseases caused by pathogenic microorganisms due to the emergence of multi-drug resistant strains. In this context, halogens, especially Iodine is known since ages for its antimicrobial activity. Therefore, especially triiodides encapsulated in organometallic complexes can be helpful as new agents against microorganisms. The aims of this work was to study the biological activity of [Na(12-Crown-4)2]I3 against gram positive Streptococcus pyogenes, Streptococcus faecalis, the spore forming bacteria Bacillus subtilis and gram negative bacteria Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa and Klebsiella pneumoniae, as well as the yeast Candida albicans. The antimicrobial and antifungal activities of the triiodide were determined by zone of inhibition plate studies. [Na(12-Crown-4)2]I3 exhibited potent antimicrobial activity on gram positive Streptochocci and the yeast C. albicans. Furthermore, the gram negative bacteria P. aeruginosa and K. pneumoniae were less effectively inhibited, while E. coli and P. mirabilis proved to be even resistant.
ARTICLE | doi:10.20944/preprints201608.0013.v1
Subject: Chemistry, Medicinal Chemistry Keywords: α-mangostin; antibacterial; antifungal; food packaging; semi-synthetic modification
Online: 2 August 2016 (09:02:09 CEST)
The microbial contamination in food packaging have been a major concern that paved the way for the search for natural based new anti-microbial agents, such as modified α-mangostin. In the present work, twelve synthetic analogs were obtained via semi-synthetic modification of α-mangostin by Ritter reaction, reduction by palladium-carbon (Pd-C), alkylation, and acetylation. The evaluation of the anti-microbial potential of the synthetic analogs showed higher therapeutic value than the parent molecule. The anti-microbial studies proved that I E showed higher antibacterial activity whereas I I showed most significant antifungal activity. Due to their microbial properties, modified α-mangostin can be utilized as active anti-microbial agents in food packaging.
ARTICLE | doi:10.20944/preprints202202.0194.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: antifungal resistance; isavuconazole; cystic fibrosis; pulmonary disease; Aspergillus fumigatus; pulmonary aspergillosis; respiratory disease; antifungal stewardship; therapeutic drug monitoring; minimum inhibitory concentration (MIC)
Online: 16 February 2022 (05:12:39 CET)
Background: The burden of resistant fungal infection is rising in patients with pulmonary disease. Options for antifungal therapy are limited, and the only orally-available antifungals, the triazoles, demonstrate inter and intra-patient variability, non-linear kinetics, toxicity, drug interactions and increasing antifungal resistance. Therapeutic drug monitoring (TDM) of itraconazole, voriconazole and posaconazole has been necessary to ensure their safety and efficacy, but is considered unnecessary for the newest triazole isavuconazole, use of which is increasing. Aims: To characterise isavuconazole susceptibility of Aspergillus fumigatus isolates in a tertiary respiratory referral centre to understand prevalence of isavuconazole antimicrobial resistance. To retrospectively review experience of isavuconazole use in this setting, assessing tolerability and therapeutic drug monitoring. Methods: A retrospective observational analysis of adult patients with respiratory disease in a tertiary hospital setting between Sept 2016 and Aug 2021. Clinical cultures were collected and triazole Minimum inhibitory concentration (MIC) were recorded (based on Clinical & Laboratory Standards Institute (CLSI method)). Isavuconazole trough drug levels were carried out as part of the standard of care. Clinical outcomes of treatment were evaluated, along with drug tolerance and TDM. Results: During the study period, isavuconazole susceptibility testing was performed on 26 Aspergillus spp isolates. 80.8% of Aspergillus fumigatus isolates were non-wild type and had isavuconazole MIC > 1mg/L, and 73.0% had MIC above the EUCAST (European Committee on Antimicrobial Susceptibility Testing) epidemiological cut-off (ECOFF) of 2mg/L. There was good correlation between isavuconazole MIC and voriconazole MIC (r =0.7, p=0.0002). 54 patients had isavuconazole therapy over the study period with a median duration of 7.7 months (IQR 0.79 - 16.42). 67% of patients were able to tolerate isavuconazole, despite toxicity with prior azole treatment being the primary indication for use (in 61.8%). Increased age (r=0.29; p=0.03 (95%CI 0.02,0.52)) and gender (r for female sex=-0.31; p=0.027 (95%CI -0.52,0.036) were associated risk factors for development of adverse events (AEs). 127 Isavuconazole TDM levels were performed over the study period with 90% >1mg/L and 72% >2mg/L. Dose change from manufacturer’s dose recommendation, however, was required in 15% of patients to achieve a serum drug concentration above the EUCAST ECOFF or Area of technical uncertainty (ATU) value of 2mg/L. Conclusion: In our study, we show use of Isavuconazole as salvage therapy in chronic pulmonary fungal disease setting with high prevalence of azole resistance. Isavuconazole MICs demonstrated good correlation with voriconazole MICs suggesting the latter could be a useful surrogate marker for isavuconazole susceptibility. Although Isavuconazole achieved excellent serum drug concentrations at standard dose compared to other azole drugs, we highlight the importance of antifungal stewardship and TDM monitoring to optimise therapy in this setting.
REVIEW | doi:10.20944/preprints202203.0262.v1
Subject: Life Sciences, Microbiology Keywords: Keywords: antifungal; azole; synergy; mycosis; resistance; Candida; dermatophytes; natural products
Online: 18 March 2022 (07:04:16 CET)
Fungal infections impact the lives of at least 12 million people every year, killing over 1.5 million. Wide-spread use of fungicides and prophylactic antifungal therapy have driven resistance in many serious fungal pathogens, and there is an urgent need to expand the current antifungal ar-senal. Recent research has focused on improving azoles, our most successful class of antifungals, by looking for synergistic interactions with secondary compounds. Synergists can co-operate with azoles by targeting steps in related pathways, or they may act on mechanisms related to re-sistance like active efflux or on totally disparate pathways or processes. A variety of sources of potential synergists have been explored, including pre-existing antimicrobials, pharmaceuticals approved for other uses, bioactive natural compounds and phytochemicals, and novel synthetic compounds. Synergy can successfully widen the antifungal spectrum, decrease inhibitory dosag-es, reduce toxicity, and prevent the development of resistance. This review highlights the diversity of mechanisms that have been exploited for the purposes of azole synergy and demonstrates that synergy remains a promising approach for meeting the urgent need for novel antifungal strate-gies.
ARTICLE | doi:10.20944/preprints202102.0539.v1
Subject: Biology, Anatomy & Morphology Keywords: Rhus chinensis Mill; Syzygium aromaticum; Rice sheath blight; Antifungal activity
Online: 24 February 2021 (10:05:28 CET)
Plant diseases reduce crop yield and quality, hampering the development of agriculture. Fungicides, which restrict chemical synthesis, are the strongest controls for plant diseases. However, the harmful effects on the environment due to continued and uncontrolled utilization of fungicides has become a major challenge in recent years. Plant-sourced fungicides are a class of plant antibacterial substances or compounds that induce plant defenses. They can kill or inhibit the growth of target pathogens efficiently with no or low toxicity, degrade readily, do not prompt development of resistance, which has led to their widespread use. In this study, the growth inhibition effect of 24 plant-sourced ethanol extracts on rice sprigs was studied. Ethanol extract of gallnuts and cloves inhibited the growth of rice sprites by up to 100%. Indoor toxicity measurement results showed that the gallnut and glove constituents inhibition reached 39.23 μg/mL and 18.82 μg/mL, respectively. Extract treated rice sprigs were dry and wrinkled. Gallnut caused intracellular swelling and breakage of mitochondria , disintegration of nuclei, aggregation of protoplasts, and complete degradation of organelles in hyphae and aggregation of cellular contents. Protection of Rhizoctonia solani viability reached 46.8% for gallnut and 37.88% for clove in water emulsions of 1,000 μg/mL gallnut and clove in the presence of 0.1% Tween 80. The protection by gallnut was significantly stronger than that of clove. The data could inform the choice of plant-sourced fungicides for the comprehensive treatment of rice sprig disease. The studied extract effectively protected rice sprigs and could be a suitable alternative to commercially available chemical fungicides. Further optimized field trials are needed to effectively sterilize rice paddies.
ARTICLE | doi:10.20944/preprints201803.0050.v1
Subject: Chemistry, Medicinal Chemistry Keywords: carboxamide; carbohydrazine; antibacterial; antifungal; molecular docking; Schiff base; NMR; IR
Online: 7 March 2018 (05:11:10 CET)
The article describes facile one-pot, hi-yielding reactions to synthesize substituted 3,4-dimethyl-1H-pyrrole-2-carboxamide (3a–m) and carbohydrazide analogues (5a–l) as potential antifungal and antimicrobial agents. The structural integrity and purity of the synthesized compounds were assigned based on appropriate spectroscopic techniques. Synthesized compounds were assessed in vitro for antifungal and antibacterial activity. The compound 5h, 5i and 5j were found to be the most potent against A. fumigatus, with MIC value of 0.031 mg/mL. The compound 5f bearing a 2,6-dichloro group on the phenyl ring was found to be the most active broad spectrum antibacterial agent with MIC value of 0.039 mg/mL. The mode of action of the most promising antifungal compounds (one representative from each series; 3j and 5h) was established by their molecular docking to the active site of sterol 14α-demethylase. Molecular docking studies revealed a highly spontaneous binding ability of the tested compounds in the access channel away from catalytic heme iron of the enzyme, which suggested that the tested compounds inhibit this enzyme and would avoid heme iron related deleterious side effects observed with existing antifungal compounds.
ARTICLE | doi:10.20944/preprints201810.0236.v1
Subject: Biology, Other Keywords: essential oils; drug resistant microorganisms; antimicrobial activity; antifungal activity; medicinal plants
Online: 11 October 2018 (11:51:16 CEST)
Antimicrobial resistance (AMR) is a recurring global problem, which constantly demands new antimicrobial compounds to challenge the resistance. It is well known that essential oils (EOs) have been known for biological activities including antimicrobial properties. In this study, EOs from seven aromatic plants of Asir region of southwestern Saudi Arabia were tested for their antimicrobial efficacy against four drug resistant pathogenic bacterial isolates (Staphylococcus aureus, Streptococcus pyogenes, Escherichia coli and Streptococcus typhimurium) and one fungal isolate (Candida albicans). Chemical compositions of EOs were determined by Gas chromatography-Mass Spectrometry (GC-MS). The results revealed that EOs from Mentha cervina, Ocimum basilicum and Origanum vulgare proved most active against all isolates with inhibitory zone range between17 to 45 mm. The lowest minimum inhibitory concentration (MIC) of 0.025mg/ml was observed for Staph. aureus and Streptococcus pyogenes with EO of Origanum vulgare. All the three EOs showed significant anti candida activity. Together form the results the EOs from Mentha cervina, Ocimum basilicum and Origanum vulgare demonstrated a significant antimicrobial efficacy against drug resistant microorganisms.
ARTICLE | doi:10.20944/preprints202212.0021.v1
Subject: Biology, Horticulture Keywords: peach (Prunus persica); postharvest preservation; antagonistic yeasts; Na-alginate film; Antifungal activity
Online: 1 December 2022 (09:50:12 CET)
Abstract: To reduce the indiscriminate use of pesticides and extend the postharvest shelf life of peach fruit (cv. Baihua) from southeast China, microbial antagonism of indigenous yeasts was mainly studied and applied in construction of composite film. After isolation, purification, cultivation and identification, a total of 14 yeast strains from 9 genera were screened out from the surface of peaches. By experimental analysis of in vitro inhibition zone and in vivo colonizing capacity, Candida oleophila sp-ELPY12B and Cryptococcus laurentii sp-ELPY15A, which have conservative structure of D1/D2 domain sequences and were considered as new species by phylogenetic analysis, were finally chosen as fungicides against the major pathogens. In combination of Na-alginate film (0.4 % glycerin as plasticizer and 0.1 % Tween-80 as emulsifier), the preservative effects of composite-treated groups (1 × 108 CFU mL−1 of Candida oleophila sp-ELPY12B and Cryptococcus laurentii sp-ELPY15A) showed best antifungal effects, which significantly delayed the postharvest preservation period about 6 - 7 d under ambient temperature of 25 ± 3°C and relative humidity of 50 - 70%.
ARTICLE | doi:10.20944/preprints202011.0167.v1
Subject: Life Sciences, Biochemistry Keywords: plant in vitro culture; plant extracts; gas chromatography; hexadecanoic acid, antifungal activity
Online: 3 November 2020 (15:26:36 CET)
Eysenhardtia platycarpa (Fabaceae) is a medicinal plant used in México and it lacks biotechnological studies for its use. The aim of this work was to establish a cell suspension cultures (CSC) of E. platycarpa, determine the phytochemical profile, and evaluate its antifungal activity. Friable callus and CSC were established with 2 mg/L 1-naphthaleneacetic acid plus 0.1 mg/L kinetin. The highest total phenolics of CSC was 15.6 mg GAE/g dry weight and the total flavonoids content ranged from 56.2 to 104.1 µg QE/g dry weight. CG‒MS analysis showed that the dichloromethane extracts of CSC, sapwood and heartwood have a high amount of hexadecanoic acid (22.3 ‒ 35.3 %) and steroids (13.5 ‒ 14.7%). Heartwood and sapwood defatted hexane extracts have the highest amount of stigmasterol (≈ 23.4%) and β-sitosterol (≈ 43%), and leaf extracts presented β-amyrin (16.3%). Methanolic leaves extracts showed mostly sugars and some polyols, mainly D-pinitol (74.3%). Dichloromethane and fatty hexane extracts of CSC exhibited the percentages inhibition higher for Sclerotium cepivorum with 71.5 and 62.0%, respectively. The maximum inhibition for Rhizoctonia solani was with fatty hexane extracts of the sapwood (51.4%). Our study suggest that CSC extracts could be used as a possible complementary alternative to synthetic fungicides.
ARTICLE | doi:10.20944/preprints202007.0438.v2
Subject: Life Sciences, Molecular Biology Keywords: structure-function relationships; enrichment analysis; antifungal activities; knottin; two-layer sandwich architecture
Online: 1 September 2020 (12:03:47 CEST)
Whether there is any inclination between structures and functions of antimicrobial peptides (AMPs) is a mystery yet to be unraveled. AMPs have various structures associated with many different antimicrobial functions, including antibacterial, anticancer, antifungal, antiparasitic and antiviral activities. However, none has yet reported any antimicrobial functional tendency within a specific category of protein/peptide structures nor any structural tendency of a specific antimicrobial function with respect to AMPs. Here we examine the relationships between structures categorized by three structural classification methods (CATH, SCOP and TM) and seven antimicrobial functions with respect to AMPs using an enrichment analysis. The results show that antifungal activities of AMPs were tightly related to two-layer sandwich structure of CATH, knottin fold of SCOP, and the first structural cluster of TM. The associations with knottin and TM cluster 1 even sustained through the AMPs with a low sequence identity. Besides, another significant mutual enrichment was observed between the third cluster of TM and anti-gram-positive-bacterial/anti-gram-negative-bacterial activities. The findings of the structure-function inclination further our understanding of AMPs and could help us design or discover new therapeutic potential AMPs.
ARTICLE | doi:10.20944/preprints201710.0194.v1
Subject: Chemistry, Medicinal Chemistry Keywords: Africa; Terminalia brownii; antifungal extracts; Aspergillus, Nattrassia, Fusarium; triterpenoids; flavonoids; ellagitannins; stilbenes
Online: 31 October 2017 (09:54:35 CET)
Decoctions, macerations and fumigations of the stem bark and wood of Terminalia brownii Fresen. are used in traditional medicine for fungal infections and as pesticides on field crops and in traditional granaries in Sudan. In addition, T. brownii is commonly used for protecting wooden houses and furniture. Therefore, using agar disc diffusion and macrodilution methods, eight extracts of various polarities from the stem wood and bark were screened for their growth inhibitory effects against filamentous fungi commonly causing fruit, vegetable and grain decay, as well as infections in the immunocompromised host. Ethyl acetate extracts of the stem wood and bark gave the best antifungal activities, with MIC values of 250 µg/ml against Nattrassia mangiferae and Fusarium verticillioides, and 500 µg/ml against Aspergillus niger and Aspergillus flavus. Aqueous extracts gave almost as potent effects as the ethyl acetate extracts against the Aspergillus and Fusarium strains, and were slightly more active than the ethyl acetate extracts against Nattrassia mangiferae. Thin layer chromatography, RP-HPLC-DAD and tandem mass spectrometry (LC-MS/MS), were employed to identify the chemical constituents in the ethyl acetate fractions of the stem bark and wood. The stem bark and wood were found to have a similar qualitative composition of polyphenols and triterpenoids, but differed quantitatively from each other. The stilbene derivatives, cis- (3) and trans- (4) resveratrol-3-O-β-galloylglucoside, were identified for the first time in T. brownii. Moreover, methyl-(S)-flavogallonate (5), quercetin-7-β-O-di-glucoside (8), quercetin-7-O-galloyl-glucoside (10), naringenin-4`-methoxy-7-pyranoside (7), 5,6-dihydroxy-3`,4`,7-tri-methoxy flavone (12), gallagic acid dilactone (terminalin) (6), a corilagin derivative (9) and two oleanane type triterpenoids (1) and (2) were characterized. Our results justify the traditional uses of macerations and decoctions of T. brownii stem wood and bark for crop and wood protection and demonstrate that standardized extracts could have uses for the eco-friendly control of plant pathogenic fungi in African agroforestry systems. Likewise, our results justify the traditional uses of these preparations for the treatment of skin infections caused by filamentous fungi.
REVIEW | doi:10.20944/preprints202101.0184.v1
Subject: Life Sciences, Biochemistry Keywords: Alzheimer’s Disease; antibacterial; anti-biofilm; antifungal; antiviral; bacteria; infectious burden; parasites; pathogens; viruses
Online: 11 January 2021 (11:28:10 CET)
Alzheimer’s disease (AD) is a chronic neurodegenerative disease associated with the overproduction and accumulation of amyloid-β peptide and hyperphosphorylation of tau proteins in the brain. Despite extensive research on the amyloid-based mechanism of AD pathogenesis, the underlying cause of AD remains poorly understood. No disease-modifying therapies currently exist, and numerous clinical trials have failed to demonstrate any benefits. The recent discovery that the amyloid-β peptide has antimicrobial activities supports the possibility of an infectious aetiology of AD and suggests that amyloid-β plaque formation might be induced by infection. AD patients have a weakened blood-brain barrier and immune system and are thus at elevated risk of microbial infections. Such infections can cause chronic neuroinflammation, production of the antimicrobial amyloid-β peptide, and neurodegeneration. Various pathogens, including viruses, bacteria, fungi, and parasites have been associated with AD. Most research in this area has focused on individual pathogens, with herpesviruses and periodontal bacteria being most frequently implicated. The purpose of this review is to highlight the potential role of multi-pathogen infections in AD. Recognition of the potential coexistence of multiple pathogens and biofilms in AD's aetiology may stimulate the development of novel approaches to its diagnosis and treatment. Multiple diagnostic tests could be applied simultaneously to detect major pathogens, followed by anti-microbial treatment using antiviral, antibacterial, antifungal, and anti-biofilm agents.
Subject: Materials Science, Nanotechnology Keywords: Amazonian fat; Ucuùba fat; Box Behnken Design; solid lipid nanoparticles; antifungal therapy; onychomycosis
Online: 23 April 2019 (12:57:42 CEST)
Ucuùba fat is fat obtained from a plant found in South America, mainly in Amazonian Brazil. Due to its biocompatibility and bioactivity, the Ucuùba fat was used for production of ketoconazole-loaded nanostructured lipid carriers (NLC) in view of an application for the treatment of onychomycosis and other persistent fungal infections. The development and optimization of the Ucuùba fat based NLC were performed using a Box-Behnken design of experiment. The independent variables were surfactant concentration (% w/v), liquid lipids concentration (% w/v), solid lipids concentration (% w/v), while the outputs of interest were particle size, polydispersity index (PDI) and drug encapsulation efficiency (EE). The Ucuùba fat based NLC were produced and the process optimized determining a predictive mathematical model. Applying the model, two formulations with the pre-required particle size, i.e., 30 and 85 nm, were produced for further evaluation. The optimized formulations were characterized and showed a particle size in agreement to the predicted value, i.e. 33.6 nm and 74.6 nm, respectively. The optimized formulations were also characterized using multiple techniques in order to investigate the solid state of drug and excipients (DSC and XRD), particle morphology (TEM) and interactions between the formulation components (FTIR). Furthermore, particle size and surface charge of the formulations was studied during a one-month stability study and did not evidence any significative modification during storage.
ARTICLE | doi:10.20944/preprints201908.0137.v1
Subject: Life Sciences, Microbiology Keywords: essential oils; Mentha x piperita; “Mentha of Pancalieri”; azoles; antifungal activity; yeasts and dermatophytes; synergism
Online: 12 August 2019 (04:52:43 CEST)
The promising antimicrobial activity of essential oils (EOs) led researchers to use them in combination with antimicrobial drugs in order to reduce drug toxicity, side effects, and resistance with single agents. In Pancalieri (Turin, Italy), there is a local production of Mentha x piperita worldwide known as “Mentha of Pancalieri”. The EO from this Mentha is considered as one of the best peppermint EO in the world. In our research, we assessed the antifungal activity of “Mentha of Pancalieri” EO either alone or in combination with azole drugs (fluconazole, itraconazole, ketoconazole) against a wide panel of yeast and dermatophyte clinical isolates. The EO was analyzed by GC-MS and its antifungal properties were evaluated by MIC/MFC parameters, according to the CLSI guidelines, with some modifications. The interaction of peppermint EO with azoles was evaluated through the chequerboard and isobologram methods. Results suggest this EO exerts a fungicidal activity against yeasts, and a fungistatic activity against dermatophytes. Interaction studies with azoles indicate mainly synergistic profiles between itraconazole and peppermint EO vs. Candida spp., Cryptococcus neoformans and Trichophyton mentagrophytes. Peppermint of Pancalieri EO may act as a potential antifungal agent and may serve as a natural adjuvant for fungal infection treatment.
ARTICLE | doi:10.20944/preprints202105.0039.v1
Subject: Chemistry, Analytical Chemistry Keywords: antifungal activity; Candida albicans; antibiofilm effect; mode of action; cytotoxicity; hemolytic assay; HOMO-LUMO; molecular electrostatic potential
Online: 5 May 2021 (12:04:01 CEST)
There is a need to search for new antifungals, especially for the treatment of the invasive Candida infections, caused mainly by C. albicans. These infections are steadily increasing at an alarming rate, mostly among immunocompromised patients. The newly synthesized compounds (3a-3k) were characterized by physico-chemical parameters and investigated for antimicrobial activity using the microdilution broth method to estimate minimal inhibitory concentration (MIC). Additionally, their antibiofilm activity and mode of action together with the effect on the membrane permeability in C. albicans were investigated. Biofilm biomass and its metabolic activity were quantitatively measured using crystal violet (CV) staining and tetrazolium salt (XTT) reduction assay. The cytotoxic effect on normal human lung fibroblasts and hemolytic effect were also evaluated. The results showed differential activity of the compounds against yeasts (MIC = 0.24-500 µg/mL) and bacteria (MIC = 125-1000 µg/mL). Most compounds possessed strong antifungal activity (MIC = 0.24-7.81 µg/mL). The compounds 3b, 3c, and 3e, showed no inhibitory (at 1/2 MIC) and eradication (at 8 x MIC) effect on C. albicans biofilm. Only slight decrease in the biofilm metabolic activity was observed for compound 3b. Moreover, the studied compounds increased the permeability of the membrane/cell wall of C. albicans and their mode of action may be related to action within the fungal cell wall structure and/or within the cell membrane. It is worth noting that the compounds had no cytotoxicity effect on pulmonary fibroblasts and erythrocytes at concentrations showing anticandidal activity. The present studies in vitro confirm that these derivatives appear to be a very promising group of antifungals for further preclinical studies.
REVIEW | doi:10.20944/preprints202301.0461.v1
Subject: Life Sciences, Microbiology Keywords: Cryptococcus; transcription factor; thermotolerance; virulence factors; antifungal; oxidative and osmotic stress; capsule; melanin; monokaryotic fruiting; mating and filamentation
Online: 26 January 2023 (02:54:41 CET)
Transcription factors are diverse intracellular proteins facilitating cellular responses to inducing factors via gene expression. Regulatory signalling cascades from the membrane proteins (sensors) to transcription factors (effectors) are paramount to accurate phenotypic display against external factors. This review examines several transcription factors germane to Cryptococcus (C.) neoformans adaptation and survival for human infection. These opportunistic pathogenic single-cell yeasts (fungi) possess several gene duplications and peculiar membrane proteins due to adaptive phenotypes and morphological plasticity. Consequently, hundreds of responsible pleiotropic genes have been studied to understand how these genes are induced, regulated, and coordinated. However, these findings are sparsely converged and interlinked, making it cumbersome to relate one gene to the other or group them by their functions. We reviewed several wide-ranging transcriptional analysis works associated with C. neoformans into comparable phenotypic traits that necessitate adaptation, survival, and human infection. We present a robust work that addresses several transcription factors and their inducing factors. Lastly, we converge, link, and group several of these factors according to their multifunctional expression pattern. We also provide adequate information on certain genes critical to this fungus, which could be explored pharmaceutically in drug targeting for more effective antifungal management.