-
Zeitschrift Fur Naturforschung. C,... May 2024Aspergillosis is one of the most common fungal infections that can threaten individuals with immune compromised condition. Due to the increasing resistance of pathogens...
Aspergillosis is one of the most common fungal infections that can threaten individuals with immune compromised condition. Due to the increasing resistance of pathogens to the existing antifungal drugs, it is difficult to tackle such disease conditions. Whereas, nikkomycin is an emerging safe and effective antifungal drug which causes fungal cell wall disruption by inhibiting chitin synthase. Hence, the study aims at the development of nikkomycin loaded PEG coated PLGA nanoparticles for its increased antifungal efficiency and inhibiting infections. The P-PLGA-Nik NPs were synthesized by w/o/w double emulsification method which resulted in a particle size of 208.3 ± 15 nm with a drug loading of 52.97 %. The NPs showed first order diffusion-controlled drug release which was sustained for 24 h. These nanoparticle's antifungal efficacy was tested using the CLSI - M61 guidelines and the MIC defined against and was found to be >32 μg/ml which was similar to the nikkomycin MIC. The hyphal tip bursting showed the fungal cell wall disruption. The non-cytotoxic and non-haemolytic nature highlights the drug safety profile.
Topics: Aspergillus flavus; Antifungal Agents; Nanoparticles; Aspergillus fumigatus; Microbial Sensitivity Tests; Chitin Synthase; Polyethylene Glycols; Polylactic Acid-Polyglycolic Acid Copolymer; Particle Size; Delayed-Action Preparations; Humans; Cell Wall; Aminoglycosides
PubMed: 38842117
DOI: 10.1515/znc-2023-0185 -
Journal of Medical Microbiology Jun 2024The fungal pathogen can induce prolonged colonization of the lungs of susceptible patients, resulting in conditions such as allergic bronchopulmonary aspergillosis and...
The fungal pathogen can induce prolonged colonization of the lungs of susceptible patients, resulting in conditions such as allergic bronchopulmonary aspergillosis and chronic pulmonary aspergillosis. Analysis of the secretome released during sub-lethal infection of larvae may give an insight into products released during prolonged human colonisation. larvae were infected with and the metabolism of host carbohydrate and proteins and production of fungal virulence factors were analysed. Label-free qualitative proteomic analysis was performed to identify fungal proteins in larvae at 96 hours post-infection and also to identify changes in the proteome as a result of infection. Infected larvae demonstrated increasing concentrations of gliotoxin and siderophore and displayed reduced amounts of haemolymph carbohydrate and protein. Fungal proteins (399) were detected by qualitative proteomic analysis in cell-free haemolymph at 96 hours and could be categorized into seven groups, including virulence ( = 25), stress response ( = 34), DNA repair and replication ( = 39), translation ( = 22), metabolism ( = 42), released intracellular ( = 28) and cellular development and cell cycle ( = 53). Analysis of the Gallerial proteome at 96 hours post-infection revealed changes in the abundance of proteins associated with immune function, metabolism, cellular structure, insect development, transcription/translation and detoxification. Characterizing the impact of the fungal secretome on the host may provide an insight into how damages tissue and suppresses the immune response during long-term pulmonary colonization.
Topics: Animals; Aspergillus fumigatus; Larva; Moths; Fungal Proteins; Secretome; Proteomics; Virulence Factors; Proteome; Hemolymph; Virulence; Aspergillosis
PubMed: 38836745
DOI: 10.1099/jmm.0.001844 -
Therapeutic Advances in Infectious... 2024, a widespread fungus in the natural environment, poses a significant threat to human health by entering the human body the airways and causing a disease called... (Review)
Review
BACKGROUND
, a widespread fungus in the natural environment, poses a significant threat to human health by entering the human body the airways and causing a disease called aspergillosis. This study comprehensively analyzed data on aspergillosis in published articles from mainland China to investigate the prevalence of , and risk factors, mortality rate, and underlying condition associated with aspergillosis.
METHODS
Published articles were retrieved from Google Scholar, PubMed, and Science Direct online search engines. In the 101 analyzed studies, 3558 isolates were meticulously collected and classified. GraphPad Prism 8 was used to statistically examine the epidemiology and clinical characteristics of aspergillosis.
RESULTS
was prominently reported ( = 2679, 75.14%), followed by ( = 437, 12.25%), ( = 219, 6.14%), and ( = 119, 3.33%). Of a total of 9810 patients, 7513 probable cases accounted for the highest number, followed by confirmed cases ( = 1956) and possible cases ( = 341). In patients, cough emerged as the most common complaint ( = 1819, 18.54%), followed by asthma ( = 1029, 10.48%) and fever (1024, 10.44%). Of total studies, invasive pulmonary aspergillosis (IPA) was reported in 47 (45.53%) studies, exhibiting an increased prevalence in Beijing ( = 12, 25.53%), Guangdong ( = 7, 14.89%), and Shanghai ( = 6, 12.76%). Chronic pulmonary aspergillosis (CPA) was reported in 14 (13.86%) studies. Among the total of 14 studies, the occurrence of CPA was 5 (35.71%) in Beijing and 3 (21.42%) in Shanghai. Allergic bronchopulmonary aspergillosis (ABPA), was reported at a lower frequency ( = 8, 7.92%), Guangdong recorded a relatively high number ( = 3, 37.5%), followed by Beijing ( = 2, 25.0%), and Shanghai ( = 1, 12.5%). Percentage of death reported: IPA had the highest rate ( = 447, 68.87%), followed by CPA ( = 181, 27.88%) and ABPA ( = 14, 2.15%). Among the aspergillosis patients, 6220 had underlying conditions, including chronic lung disease ( = 3765, 60.53%), previous tuberculosis ( = 416, 6.68%), and organ transplant or organ failure ( = 648, 10.41%). Aspergillosis was also found in patients using corticosteroid therapy ( = 622, 10.0%).
CONCLUSION
This review sheds light on the prevalence patterns of species, risk factors of aspergillosis, and gaps in surveillance that could be helpful for the control and treatment of aspergillosis and guide the researchers in future studies.
REGISTRATION
This systematic review was prospectively registered on PROSPERO: Registration ID CRD42023476870.
PubMed: 38835831
DOI: 10.1177/20499361241252537 -
MBio Jun 2024Group III hybrid histidine kinases are fungal-specific proteins and part of the multistep phosphorelay, representing the initial part of the high osmolarity glycerol...
UNLABELLED
Group III hybrid histidine kinases are fungal-specific proteins and part of the multistep phosphorelay, representing the initial part of the high osmolarity glycerol (HOG) pathway. TcsC, the corresponding kinase in was expected to be a cytosolic protein but is targeted to the nucleus. Activation of TcsC by the antifungal fludioxonil has lethal consequences for the fungus. The agent triggers a fast and TcsC-dependent activation of SakA and later on a redistribution of TcsC to the cytoplasm. High osmolarity also activates TcsC, which then exits the nucleus or concentrates in spot-like, intra-nuclear structures. The sequence corresponding to the N-terminal 208 amino acids of TcsC lacks detectable domains. Its loss renders TcsC cytosolic and non-responsive to hyperosmotic stress, but it has no impact on the antifungal activity of fludioxonil. A point mutation in one of the three putative nuclear localization sequences, which are present in the N-terminus, prevents the nuclear localization of TcsC, but not its ability to respond to hyperosmotic stress. Hence, this striking intracellular localization is no prerequisite for the role of TcsC in the adaptive response to hyperosmotic stress, instead, TcsC proteins that are present in the nuclei seem to modulate the cell wall composition of hyphae, which takes place in the absence of stress. The results of the present study underline that the spatiotemporal dynamics of the individual components of the multistep phosphorelay is a crucial feature of this unique signaling hub.
IMPORTANCE
Signaling pathways enable pathogens, such as , to respond to a changing environment. The TcsC protein is the major sensor of the high osmolarity glycerol (HOG) pathway of and it is also the target of certain antifungals. Insights in its function are therefore relevant for the pathogenicity and new therapeutic treatment options. TcsC was expected to be cytoplasmic, but we detected it in the nucleus and showed that it translocates to the cytoplasm upon activation. We have identified the motif that guides TcsC to the nucleus. An exchange of a single amino acid in this motif prevents a nuclear localization, but this nuclear targeting is no prerequisite for the TcsC-mediated stress response. Loss of the N-terminal 208 amino acids prevents the nuclear localization and renders TcsC unable to respond to hyperosmotic stress demonstrating that this part of the protein is of crucial importance.
PubMed: 38832777
DOI: 10.1128/mbio.01184-24 -
Indian Journal of Medical Microbiology Jun 2024Due to the potential for Aspergillus species to cause lethal infections and the rising rates of antifungal resistance, the significance of antifungal susceptibility...
PURPOSE
Due to the potential for Aspergillus species to cause lethal infections and the rising rates of antifungal resistance, the significance of antifungal susceptibility tests has increased. We aimed to assess the sensitivities of Aspergillus species to amphotericin B (AMB), voriconazole (VOR), itraconazole (ITZ), and caspofungin (CAS) using disk diffusion (DD) and gradient diffusion (GD) methods and compare them with broth microdilution (BMD) as the reference susceptibility method.
METHODS
The study involved 62 Aspergillus fumigatus, 28 Aspergillus flavus, and 16 Aspergillus terreus isolates, totaling 106 Aspergillus isolates. BMD and DD methods were performed in accordance with CLSI M38-A2 and CLSI M51-A documents, respectively. The GD method utilized nonsupplemented Mueller Hinton agar (MHA) as the medium.
RESULTS
In the BMD method, the lowest minimal inhibitory concentration (MIC) or minimal effective concentration (MEC) values were observed for VOR and CAS (0.5 μg/mL and 0.06 μg/mL, respectively). AMB and ITZ MIC values were both 2 μg/mL. In our comparison of the GD method with the BMD method at ±2 dilution, we observed essential agreement rates of 91.6%, 99.1%, 100%, and 38.6% for AMB, VOR, ITZ, and CAS, respectively. When comparing DD and BMD methods, we found categorical agreement rates of 65.1%, 99.1%, 77.3%, and 100% for AMB, VOR, ITZ, and CAS, respectively. For GD and BMD methods, these rates were 79.2%, 99.1%, 87.8%, and 100%.
CONCLUSIONS
Given the high essential and categorical agreement rates, we posit that the GD method is a viable alternative to the BMD method for AMB, ITZ and VOR but not for CAS. In addition, the use of nonsupplemented MHA in the GD method proves advantageous due to its cost-effectiveness and widespread availability compared to other growth media.
PubMed: 38830536
DOI: 10.1016/j.ijmmb.2024.100642 -
Infection and Drug Resistance 2024Azole resistance in poses a significant challenge in the management of invasive aspergillosis. This study aimed to investigate the antifungal susceptibility and...
PURPOSE
Azole resistance in poses a significant challenge in the management of invasive aspergillosis. This study aimed to investigate the antifungal susceptibility and mutation profiles of isolates in Malaysia.
PATIENTS AND METHODS
Sixty clinical isolates were collected and subjected to antifungal susceptibility testing (AFST) and molecular analysis. The antifungal susceptibility testing was performed according to CLSI M38 guideline. The geometric mean (GM) minimum inhibitory concentration (MIC), MIC/MIC for voriconazole, itraconazole, posaconazole, amphotericin B, and isavuconazole against in non-invasive cases and invasive cases were calculated. In addition, the presence of mutations was also identified.
RESULTS
The present study revealed an overall resistance rate of 6.7% among the isolates. In non-invasive cases, isavuconazole and posaconazole demonstrated the lowest GM MIC of 0.08 µg/mL. Following them were itraconazole, voriconazole, and amphotericin B with concentrations of 0.15µg/mL, 0.16µg/mL and 0.90µg/mL, respectively. Similarly, in invasive cases, isavuconazole and posaconazole exhibited the lowest GM MIC of 0.09µg/mL. Following them were itraconazole, voriconazole, and amphotericin B with concentrations of 0.14µg/mL, 0.17µg/mL and 0.80µg/mL, respectively. Genotypic analysis revealed various mutations, including F46Y, M172V, N248K, R34L, V244A, V244S, and E427K. However, not all mutations corresponded to antifungal resistance.
CONCLUSION
The majority of clinical isolates demonstrated susceptibility to the antifungal agents tested, with isavuconazole and posaconazole demonstrating the lowest MIC values. However, mutations were discovered without a consistent correlation to antifungal resistance, emphasising the need for additional research.
PubMed: 38828376
DOI: 10.2147/IDR.S452619 -
Cell Surface (Amsterdam, Netherlands) Jun 2024Cell wall biomass, Earth's most abundant natural resource, holds significant potential for sustainable biofuel production. Composed of cellulose, hemicellulose, lignin,... (Review)
Review
Cell wall biomass, Earth's most abundant natural resource, holds significant potential for sustainable biofuel production. Composed of cellulose, hemicellulose, lignin, pectin, and other polymers, the plant cell wall provides essential structural support to diverse organisms in nature. In contrast, non-plant species like insects, crustaceans, and fungi rely on chitin as their primary structural polysaccharide. The saprophytic fungus has been widely recognized for its adaptability to various environmental conditions. It achieves this by secreting different cell wall biomass degradation enzymes to obtain essential nutrients. This review compiles a comprehensive collection of cell wall degradation enzymes derived from , including cellulases, hemicellulases, various chitin degradation enzymes, and other polymer degradation enzymes. Notably, these enzymes exhibit biochemical characteristics such as temperature tolerance or acid adaptability, indicating their potential applications across a spectrum of industries.
PubMed: 38827922
DOI: 10.1016/j.tcsw.2024.100126 -
Journal of Family Medicine and Primary... Apr 2024SARS-COV virus operates as a significant risk factor for invasive fungal aspergillosis and mucormycosis. Successful management of this fulminant infection requires early...
BACKGROUND
SARS-COV virus operates as a significant risk factor for invasive fungal aspergillosis and mucormycosis. Successful management of this fulminant infection requires early recognition of the disease and aggressive medical or surgical interventions to prevent the high morbidity and mortality associated with the disease process.
AIMS AND OBJECTIVE OF THE STUDY
1. To isolate and identify different species of fungi among acute rhinosinusitis patients. 2. To assess the association of risk factors causing fungal rhinosinusitis. 3. To assess the changing trend in fungal rhinosinusitis during the COVID era.
MATERIAL AND METHODS
This is a retrospective observational study conducted from May 2020 to October 2022, attending the ENT department and relevant data were collected from the medical records department of ABVIMS and Dr RML Hospital, New Delhi, a Tertiary Care Referral Centre in India. The major risk factors studied were age, gender, COVID-19 infection and underlying diseases (such as diabetes mellitus, ischaemic heart disease, hypertension, malignancies, chronic kidney DISEASES, etc.); details of corticosteroid use of all patients were recorded in the datasheet. The pandemic data was divided into three distinct time periods/waves/eras, i.e., first, second, and third waves, each of which included ten months, to examine the changing trend in fungal rhinosinusitis in the pandemic era of COVID-19.
RESULTS
A total of 412 patients out of which 236 patients were clinically diagnosed with fungal sinusitis based on revised EORTC criteria. The most common site involved was the orbit with paranasal sinus and eye 86/236 (36.4%), followed by involvement of nasal and paranasal sinus alone 68/236 (28.8%). The most prevalent age range affected was 40 to 50 years. The most commonly associated comorbidity was diabetes mellitus (DM) in 176 (74.5%), followed by head and neck malignancies in 22 (9.32%) patients. Thirty-eight (50.6%) species and 18 (24%) were the most common isolated fungal species on culture, followed by spp. 14 (18.6%) and 5 (6.6%) in the period. In the second wave of COVID, there was a surge in cases 36 (45%) and after the second wave, the cases increased by 14 (19%) during Jan-Oct 2022.
CONCLUSION
With the continuing coronavirus pandemic, there is an unprecedented and discernible rise in the prevalence of acute invasive fungal sinusitis certainly a spike in cases of Aspergillus infection was observed, probably due to unprecedented usage of Amphotericin B for the treatment of mucormycosis during the third wave This underlines the importance of the need to tailor our treatment protocol as per the etiological agents hence the right antifungal drugs combined with urgent surgical procedures on a case-to-case basis may certainly increase the chances of survival.
PubMed: 38827671
DOI: 10.4103/jfmpc.jfmpc_871_23 -
BioRxiv : the Preprint Server For... May 2024Treatment of fungal infections associated with the filamentous fungus is becoming more problematic as this organism is developing resistance to the main...
Treatment of fungal infections associated with the filamentous fungus is becoming more problematic as this organism is developing resistance to the main chemotherapeutic drug at an increasing rate. Azole drugs represent the current standard-of-care in treatment of aspergillosis with this drug class acting by inhibiting a key step in biosynthesis of the fungal sterol ergosterol. Azole compounds block the activity of the lanosterol α-14 demethylase, encoded by the gene. A common route of azole resistance involves an increase in transcription of . This transcriptional increase requires the function of a Zn2Cys6 DNA-binding domain-containing transcription activator protein called AtrR. AtrR was identified through its action as a positive regulator of expression of an ATP-binding cassette transporter (/ here called ). Using both deletion and alanine scanning mutagenesis, we demonstrate that a conserved C-terminal domain in is required for expression of but dispensable for transcription. This domain is also found in several other fungal pathogen AtrR homologues consistent with a conserved gene-selective function of this protein segment being conserved. Using RNA-seq, we find that this gene-specific transcriptional defect extends to several other membrane transporter-encoding genes including a second ABC transporter locus. Our data reveal that AtrR uses at least two distinct mechanisms to induce gene expression and that normal susceptibility to azole drugs cannot be provided by maintenance of wild-type expression of the ergosterol biosynthetic pathway when ABC transporter expression is reduced.
PubMed: 38826412
DOI: 10.1101/2024.05.22.595332 -
Microbial Cell Factories May 2024Multi resistant fungi are on the rise, and our arsenal compounds are limited to few choices in the market such as polyenes, pyrimidine analogs, azoles, allylamines, and... (Review)
Review
Multi resistant fungi are on the rise, and our arsenal compounds are limited to few choices in the market such as polyenes, pyrimidine analogs, azoles, allylamines, and echinocandins. Although each of these drugs featured a unique mechanism, antifungal resistant strains did emerge and continued to arise against them worldwide. Moreover, the genetic variation between fungi and their host humans is small, which leads to significant challenges in new antifungal drug discovery. Endophytes are still an underexplored source of bioactive secondary metabolites. Many studies were conducted to isolate and screen endophytic pure compounds with efficacy against resistant yeasts and fungi; especially, Candida albicans, C. auris, Cryptococcus neoformans and Aspergillus fumigatus, which encouraged writing this review to critically analyze the chemical nature, potency, and fungal source of the isolated endophytic compounds as well as their novelty features and SAR when possible. Herein, we report a comprehensive list of around 320 assayed antifungal compounds against Candida albicans, C. auris, Cryptococcus neoformans and Aspergillus fumigatus in the period 1980-2024, the majority of which were isolated from fungi of orders Eurotiales and Hypocreales associated with terrestrial plants, probably due to the ease of laboratory cultivation of these strains. 46% of the reviewed compounds were active against C. albicans, 23% against C. neoformans, 29% against A. fumigatus and only 2% against C. auris. Coculturing was proved to be an effective technique to induce cryptic metabolites absent in other axenic cultures or host extract cultures, with Irperide as the most promising compounds MIC value 1 μg/mL. C. auris was susceptible to only persephacin and rubiginosin C. The latter showed potent inhibition against this recalcitrant strain in a non-fungicide way, which unveils the potential of fungal biofilm inhibition. Further development of culturing techniques and activation of silent metabolic pathways would be favorable to inspire the search for novel bioactive antifungals.
Topics: Antifungal Agents; Endophytes; Humans; Microbial Sensitivity Tests; Cryptococcus neoformans; Fungi; Aspergillus fumigatus; Candida albicans
PubMed: 38822407
DOI: 10.1186/s12934-024-02411-3