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Antimicrobial Agents and Chemotherapy Feb 2024Manogepix is a potent new antifungal agent targeting the fungal Gwt1 enzyme. Manogepix has previously demonstrated potent activity against clinical isolates of both...
Manogepix is a potent new antifungal agent targeting the fungal Gwt1 enzyme. Manogepix has previously demonstrated potent activity against clinical isolates of both (except ) and species. This study determined the activity of manogepix and comparators against a large collection of infrequently encountered yeast and molds. Manogepix demonstrated potent activity against infrequently encountered yeasts exhibiting elevated MIC values to other drug classes, including spp. (MIC, 0.008/0.12 mg/L), () (MIC, 0.03/0.06 mg/L), (MIC, 0.016-0.06 mg/L), (MIC, 0.016 mg/L), and (MIC, 0.03/0.12 mg/L). Similarly, manogepix was active against infrequently encountered mold isolates and strains exhibiting elevated MIC/MEC values to echinocandins, azoles, and amphotericin B, including (MEC, 0.004 mg/L), spp. (MEC, 0.016/0.06 mg/L), () species complex (MEC, 0.016/0.03 mg/L), (MEC, 0.03/0.06 mg/L), (MEC, 0.008 mg/L), spp. (MEC, ≤0.008/0.016 mg/L), (MEC, 0.06 mg/L), (MEC range, 0.016-0.12 mg/L), and spp. (MEC, 0.03/0.06 mg/L). Manogepix demonstrated potent activity against a majority of the infrequently encountered yeast and mold isolates tested including strains with elevated MIC/MEC values to other drug classes. Additional clinical development of manogepix (fosmanogepix) in difficult-to-treat, resistant fungal infections is warranted.
Topics: Triazoles; Antifungal Agents; Fungi; Aminopyridines; Yeasts; Candida; Microbial Sensitivity Tests; Isoxazoles
PubMed: 38205999
DOI: 10.1128/aac.01132-23 -
BMC Genomics Jun 2024The search for new bioactive natural compounds with anticancer activity is still of great importance. Even though their potential for diagnostics and treatment of cancer...
BACKGROUND
The search for new bioactive natural compounds with anticancer activity is still of great importance. Even though their potential for diagnostics and treatment of cancer has already been proved, the availability is still limited. Hypericin, a naphthodianthrone isolated essentially from plant source Hypericum perforatum L. along with other related anthraquinones and bisanthraquinones belongs to this group of compounds. Although it has been proven that hypericin is synthesized by the polyketide pathway in plants, none of the candidate genes coding for key enzymes has been experimentally validated yet. Despite the rare occurrence of anthraquinones in plants, their presence in microorganisms, including endophytic fungi, is quite common. Unlike plants, several biosynthetic genes grouped into clusters (BGCs) in fungal endophytes have already been characterized.
RESULTS
The aim of this work was to predict, identify and characterize the anthraquinone BGCs in de novo assembled and functionally annotated genomes of selected endophytic fungal isolates (Fusarium oxysporum, Plectosphaerella cucumerina, Scedosporium apiospermum, Diaporthe eres, Canariomyces subthermophilus) obtained from different tissues of Hypericum spp. The number of predicted type I polyketide synthase (PKS) BGCs in the studied genomes varied. The non-reducing type I PKS lacking thioesterase domain and adjacent discrete gene encoding protein with product release function were identified only in the genomes of C. subthermophilus and D. eres. A candidate bisanthraquinone BGC was predicted in C. subthermophilus genome and comprised genes coding the enzymes that catalyze formation of the basic anthraquinone skeleton (PKS, metallo-beta-lactamase, decarboxylase, anthrone oxygenase), putative dimerization enzyme (cytochrome P450 monooxygenase), other tailoring enzymes (oxidoreductase, dehydrogenase/reductase), and non-catalytic proteins (fungal transcription factor, transporter protein).
CONCLUSIONS
The results provide an insight into genetic background of anthraquinone biosynthesis in Hypericum-borne endophytes. The predicted bisanthraquinone gene cluster represents a basis for functional validation of the candidate biosynthetic genes in a simple eukaryotic system as a prospective biotechnological alternative for production of hypericin and related bioactive anthraquinones.
Topics: Hypericum; Multigene Family; Polyketides; Endophytes; Anthraquinones; Fungi; Genome, Fungal; Computer Simulation; Polyketide Synthases; Perylene; Anthracenes; Genomics; Phylogeny
PubMed: 38831295
DOI: 10.1186/s12864-024-10475-z -
Therapeutic Advances in Respiratory... 2024A significant decline in pulmonary exacerbation rates has been reported in CF patients homozygous for F508del treated with lumacaftor/ivacaftor. However, it is still...
BACKGROUND
A significant decline in pulmonary exacerbation rates has been reported in CF patients homozygous for F508del treated with lumacaftor/ivacaftor. However, it is still unclear whether this reduction reflects a diminished microbiological burden.
OBJECTIVES
The aim of this study was to determine the impact of lumacaftor/ivacaftor on the bacterial and fungal burden.
DESIGN
The study is a prospective multicenter cohort study including 132 CF patients homozygous for F508del treated with lumacaftor/ivacaftor.
METHODS
Clinical parameters as well as bacterial and fungal outcomes 1 year after initiation of lumacaftor/ivacaftor were compared to data from 2 years prior to initiation of the treatment. Changes in the slope of the outcomes before and after the onset of treatment were assessed.
RESULTS
Lung function measured as ppFEV1 ( < 0.001), body mass index (BMI) in adults ( < 0.001), and BMI -score in children ( = 0.007) were improved after initiation of lumacaftor/ivacaftor. In addition, the slope of the prevalence of ( = 0.007) and ( < 0.001) shifted from positive to negative, that is, became less prevalent, 1 year after treatment, while the slope for ( = 0.009), spp ( = 0.026), and ( < 0.001) shifted from negative to positive.
CONCLUSION
The current study showed a significant improvement in clinical parameters and a reduction of some of CF respiratory microorganisms 1 year after starting with lumacaftor/ivacaftor. However, no significant changes were observed for , or , key pathogens in the CF context.
Topics: Humans; Cystic Fibrosis; Male; Prospective Studies; Female; Aminophenols; Benzodioxoles; Child; Adult; Young Adult; Adolescent; Drug Combinations; Aminopyridines; Quinolones; Sweden; Treatment Outcome; Mycoses; Respiratory Tract Infections; Cystic Fibrosis Transmembrane Conductance Regulator; Lung; Chloride Channel Agonists; Time Factors; Fungi; Bacterial Infections
PubMed: 38780228
DOI: 10.1177/17534666241254090 -
Medical Mycology Jan 2024Infections with Scedosporium spp. are emerging in the past two decades and are associated with a high mortality rate. Microbiological detection can be associated with...
Infections with Scedosporium spp. are emerging in the past two decades and are associated with a high mortality rate. Microbiological detection can be associated with either colonization or infection. Evolution from colonization into infection is difficult to predict and clinical management upon microbiological detection is complex. Microbiological samples from 2015 to 2021 were retrospectively analyzed in a single tertiary care center. Classification into colonization or infection was performed upon first microbiological detection. Clinical evolution was observed until July 2023. Further diagnostic procedures after initial detection were analyzed. Among 38 patients with microbiological detection of Scedosporium spp., 10 were diagnosed with an infection at the initial detection and two progressed from colonization to infection during the observation time. The main sites of infection were lung (5/12; 41.6%) followed by ocular sites (4/12; 33.3%). Imaging, bronchoscopy or biopsies upon detection were performed in a minority of patients. Overall mortality rate was similar in both groups initially classified as colonization or infection [30.7% and 33.3%, respectively (P = 1.0)]. In all patients where surgical debridement of site of infection was performed (5/12; 42%); no death was observed. Although death occurred more often in the group without eradication (3/4; 75%) compared with the group with successful eradication (1/8; 12.5%), statistical significance could not be reached (P = 0.053). As therapeutic management directly impacts patients' outcome, a multidisciplinary approach upon microbiological detection of Scedosporium spp. should be encouraged. Data from larger cohorts are warranted in order to analyze contributing factors favoring the evolution from colonization into infection.
Topics: Humans; Retrospective Studies; Scedosporium; Antifungal Agents; Clinical Relevance; Risk Factors
PubMed: 38242842
DOI: 10.1093/mmy/myae002 -
Nanomaterials (Basel, Switzerland) May 2024Recently, nanoparticles have been widely used in agricultural pest control as a secure substitute for pesticides. However, the effect of nanoparticles on controlling the...
Termiticidal Effects and Morpho-Histological Alterations in the Subterranean Termite () Induced by Biosynthesized Zinc Oxide, Titanium Dioxide, and Chitosan Nanoparticles.
Recently, nanoparticles have been widely used in agricultural pest control as a secure substitute for pesticides. However, the effect of nanoparticles on controlling the subterranean termite () has not been studied yet. Consequently, this study aimed to evaluate the effectiveness of some nanomaterials in controlling . The results showed that zinc oxide nanoparticles (ZnONPs), titanium dioxide nanoparticles (TiONPs), and chitosan nanoparticles (CsNPs) biosynthesized using the culture filtrate of () had an effective role in controlling . Moreover, the mortality rate of after 48 h of treatment with ZnONPs, TiONPs, and CsNPs at a 1000 µg/mL concentration was 100%, 100%, and 97.67%, respectively. Furthermore, using ZnONPs, TiONPs, and CsNPs on resulted in morpho-histological variations in the normal structure, leading to its death. X-ray diffraction, UV-vis spectroscopy, Fourier transform infrared spectroscopy, scanning electron microscopy, dynamic light scattering, energy dispersive spectroscopy, and the Zeta potential were used to characterize the biosynthesis of ZnONPs, TiONPs, and CsNPs with strong activity against termites. Overall, the results of this investigation suggest that biosynthesized ZnONPs, TiONPs, and CsNPs have enormous potential for use as innovative, ecologically safe pesticides for control.
PubMed: 38869552
DOI: 10.3390/nano14110927