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characterization of a polyethylene glycol-amphotericin b conjugate loaded with free amb for improved antifungal efficacy.amphotericin b (amb) is a highly hydrophobic antifungal, whose use is limited by its toxicity and poor solubility. to improve its solubility, amb was reacted with a functionalized polyethylene glycol (peg), yielding soluble complex amb-peg formulations that theoretically comprise of chemically conjugated amb-peg and free amb that is physically associated with the conjugate. reverse-phase chromatography and size exclusion chromatography methods using hplc were developed to separate conjugated amb ...201627008086
new claims for wild carrot (daucus carota subsp. carota) essential oil.the essential oil of daucus carota subsp. carota from portugal, with high amounts of geranyl acetate (29.0%), α-pinene (27.2%), and 11αh-himachal-4-en-1β-ol (9.2%), was assessed for its biological potential. the antimicrobial activity was evaluated against several gram-positive and gram-negative bacteria, yeasts, dermatophytes, and aspergillus strains. the minimal inhibitory concentration (mic) and minimal lethal concentration (mlc) were evaluated showing a significant activity towards gram-posi ...201626981143
inhibition of bacterial and fungal pathogens by the orphaned drug auranofin.we identified auranofin as an antimicrobial compound utilizing a high-throughput screen using a caenorhabditis elegans-staphylococcus aureus infection model. results/methodology: treatment of infected nematodes with auranofin resulted in a prolonged survival rate of 95%, reached with 0.78 μg/ml. further investigation of the antimicrobial activity of auranofin found inhibition against s. aureus, enterococcus faecium and enterococcus faecalis. importantly, the fungal pathogens cryptococcus neoform ...201626808006
mechanism of antifungal activity of antimicrobial peptide app, a cell-penetrating peptide derivative, against candida albicans: intracellular dna binding and cell cycle arrest.we investigated the antifungal properties and anti-candidal mechanism of antimicrobial peptide app. the minimum inhibitory concentration of app was 8 μm against candida albicans and aspeogillus flavus, the concentration against saccharomyces cerevisiae and cryptococcus neoformans was 16 μm, while 32 μm inhibited aspergilla niger and trichopyton rubrum. app caused slight depolarization (12.32 ± 0.87%) of the membrane potential of intact c. albicans cells when it exerted its anti-candidal activity ...201626743655
lysine enhances the effect of amphotericin b against candida albicans in vitro.amphotericin b (amb) is a polyene antibiotic produced by streptomyces nodosus and has been used for >50 years in the treatment of acute systemic fungal infections. in the present study, we demonstrated that lysine, an essential amino acid, could enhance the effect of amb against candida albicans in vitro, although lysine itself did not exert a fungicidal effect. in addition, the combination of amb with lysine could provide an enhanced action against candida parapsilosis and cryptococcus neoforma ...201626711896
cryptococcus flips its lid - membrane phospholipid asymmetry modulates antifungal drug resistance and virulence.human fungal infections are increasing in prevalence and acquisition of antifungal drug resistance, while our antifungal drug armamentarium remains very limited, constituting a significant public health problem. despite the fact that prominent antifungal drugs target the fungal cell membrane, very little is known about how fungal membrane biology regulates drug-target interactions. asymmetrical phospholipid distribution is an essential property of biological membranes, which is maintained by a g ...201628357373
first case of mixed infection with cryptococcus deuterogattii and cryptococcus neoformans vni in an ivorian hiv-positive patient.cryptococcal meningitis (cm) may be caused by several species of cryptococcus.201628348767
erratum for voelz et al., cytokine signaling regulates the outcome of intracellular macrophage parasitism by cryptococcus neoformans. 201627864424
genomic epidemiology of cryptococcus yeasts identifies adaptation to environmental niches underpinning infection across an african hiv/aids cohort.emerging infections caused by fungi have become a widely recognized global phenomenon and are causing an increasing burden of disease. genomic techniques are providing new insights into the structure of fungal populations, revealing hitherto undescribed fine-scale adaptations to environments and hosts that govern their emergence as infections. cryptococcal meningitis is a neglected tropical disease that is responsible for a large proportion of aids-related deaths across africa; however, the ecol ...201627862555
high-resolution genetics identifies the lipid transfer protein sec14p as target for antifungal ergolines.invasive infections by fungal pathogens cause more deaths than malaria worldwide. we found the ergoline compound ngx04 in an antifungal screen, with selectivity over mammalian cells. high-resolution chemogenomics identified the lipid transfer protein sec14p as the target of ngx04 and compound-resistant mutations in sec14p define compound-target interactions in the substrate binding pocket of the protein. beyond its essential lipid transfer function in a variety of pathogenic fungi, sec14p is als ...201627855158
putative orotate transporter of cryptococcus neoformans, oat1, is a member of the ncs1/prt transporter super family and its loss causes attenuation of virulence.it is well known that 5-fluoroorotic acid (5-foa)-resistant mutants isolated from wild-type cryptococcus neoformans are exclusively either ura3 or ura5 mutants. unexpectedly, many of the 5-foa-resistant mutants isolated in our selective regime were ura(+). we identified cnm00460 as the gene responsible for these mutations. cnm00460 belongs to the nucleobase cation symporter 1/purine-related transporter (ncs1/prt) super family of fungal transporters, representative members of which are uracil tra ...201628011993
discovery and characterization of a peptoid with antifungal activity against cryptococcus neoformans.studies show there is an increasing rate of fungal infections, especially in immunocompromised patients and treatments for fungal genera, such as aspergillus, candida, and cryptococcus, carry significant cytotoxicity with an increasing prevalence of antifungal resistance. we have previously reported a high-throughput assay for identifying peptoids with antimicrobial properties from combinatorial libraries. here we report the application of this assay in identifying a peptoid with antifungal prop ...201627994753
distribution of the o-acetyl groups and β-galactofuranose units in galactoxylomannans of the opportunistic fungus cryptococcus neoformans.galactoxylomannans (galxms) are a mixture of neutral and acidic capsular polysaccharides produced by the opportunistic fungus cryptococcus neoformans that exhibit potent suppressive effects on the host immune system. previous studies describing the chemical structure of c. neoformans galxms have reported species without o-acetyl substituents. herein we describe that c. neoformans grown in capsule-inducing medium produces highly o-acetylated galxms. the location of the o-acetyl groups was determi ...201627986834
primary cutaneous cryptococcal infection with subsequent erythema nodosum in a 10-year-old immunocompetent girl. 201627981228
integrated activity and genetic profiling of secreted peptidases in cryptococcus neoformans reveals an aspartyl peptidase required for low ph survival and virulence.the opportunistic fungal pathogen cryptococcus neoformans is a major cause of mortality in immunocompromised individuals, resulting in more than 600,000 deaths per year. many human fungal pathogens secrete peptidases that influence virulence, but in most cases the substrate specificity and regulation of these enzymes remains poorly understood. the paucity of such information is a roadblock to our understanding of the biological functions of peptidases and whether or not these enzymes are viable ...201627977806
investigating conservation of the cell-cycle-regulated transcriptional program in the fungal pathogen, cryptococcus neoformans.the pathogenic yeast cryptococcus neoformans causes fungal meningitis in immune-compromised patients. cell proliferation in the budding yeast form is required for c. neoformans to infect human hosts, and virulence factors such as capsule formation and melanin production are affected by cell-cycle perturbation. thus, understanding cell-cycle regulation is critical for a full understanding of virulence factors for disease. our group and others have demonstrated that a large fraction of genes in sa ...201627918582
csn1201, a subunit of the cop9 signalosome, regulates the virulence in cryptococcus neoformans infection.the cop9 signalosome (csn) is a multisubunit protein complex, and it now has been found to participate in diverse cellular and developmental processes in various eukaryotic organisms. cryptococcus neoformans (c. neoformans) is an important basidiomycete pathogen that causes life-threatening meningoencephalitis primarily in the immune compromised population. here, we generated csn deletion mutants to investigate the role in cryptococcus infection. compared to other csn mutants, we identified a cs ...201627915049
unraveling fungal radiation resistance regulatory networks through the genome-wide transcriptome and genetic analyses of cryptococcus neoformans.the basidiomycetous fungus cryptococcus neoformans has been known to be highly radiation resistant and has been found in fatal radioactive environments such as the damaged nuclear reactor at chernobyl. to elucidate the mechanisms underlying the radiation resistance phenotype of c. neoformans, we identified genes affected by gamma radiation through genome-wide transcriptome analysis and characterized their functions. we found that genes involved in dna damage repair systems were upregulated in re ...201627899501
systemic approach to virulence gene network analysis for gaining new insight into cryptococcal virulence.cryptococcus neoformans is pathogenic yeast, responsible for highly lethal infections in compromised patients around the globe. c. neoformans typically initiates infections in mammalian lung tissue and subsequently disseminates to the central nervous system where it causes significant pathologies. virulence genes of c. neoformans are being characterized at an increasing rate, however, we are far from a comprehensive understanding of their roles and genetic interactions. some of these reported vi ...201627833589
environmental distribution of cryptococcus neoformans and c. gattii around the mediterranean basin. 201627789540
the putative autophagy regulator atg7 affects the physiology and pathogenic mechanisms of cryptococcus neoformans.we investigated the involvement of the autophagy protein 7 (atg7) in physiology and pathogenic potential of cryptococcus neoformans.201627750454
antifungal activity of eicosanoic acids isolated from the endophytic fungus mycosphaerella sp. against cryptococcus neoformans and c. gattii.the antifungal effects of two eicosanoic acids, 2-amino-3,4-dihydroxy-2-25-(hydroxymethyl)-14-oxo-6,12-eicosenoic acid (compound 1) and myriocin (compound 2), isolated from mycosphaerella sp. were evaluated against cryptococcus neoformans and c. gattii. the compounds displayed antifungal activities against several isolates of c. neoformans and c. gattii, with minimal inhibitory concentration (mic) values ranging from 0.49 to 7.82 μm for compound 1 and 0.48-1.95 μm for compound 2. in the checkerb ...201627693577
cryptococcal cellulitis in a heart transplant recipient. 201627766302
identification and characterization of vni/vnii and novel vnii/vniv hybrids and impact of hybridization on virulence and antifungal susceptibility within the c. neoformans/c. gattii species complex.cryptococcus neoformans and c. gattii are pathogenic basidiomycetous yeasts and the commonest cause of fungal infection of the central nervous system. cryptococci are typically haploid but several inter-species, inter-varietal and intra-varietal hybrids have been reported. it has a bipolar mating system with sexual reproduction occurring normally between two individuals with opposite mating types, α and a. this study set out to characterize hybrid isolates within the c. neoformans/c. gattii spec ...201627764108
mode of action of a designed antimicrobial peptide: high potency against cryptococcus neoformans.there is a significant need for developing compounds that kill cryptococcus neoformans, the fungal pathogen that causes meningoencephalitis in immunocompromised individuals. here, we report the mode of action of a designed antifungal peptide, vg16krkp (vargwkrkcplfgkgg) against c. neoformans. it is shown that vg16krkp kills fungal cells mainly through membrane compromise leading to efflux of ions and cell metabolites. intracellular localization, inhibition of in vitro transcription, and dna bind ...201627760359
disruption of de novo adenosine triphosphate (atp) biosynthesis abolishes virulence in cryptococcus neoformans.opportunistic fungal pathogens such as cryptococcus neoformans are a growing cause of morbidity and mortality among immunocompromised populations worldwide. to address the current paucity of antifungal therapeutic agents, further research into fungal-specific drug targets is required. adenylosuccinate synthetase (adss) is a crucial enzyme in the adeosine triphosphate (atp) biosynthetic pathway, catalyzing the formation of adenylosuccinate from inosine monophosphate and aspartate. we have investi ...201627759389
distribution and association between environmental and clinical isolates of cryptococcus neoformans in bogotá-colombia, 2012-2015.the propagules of the fungal species cryptococcus neoformans and c. gattii, whose varieties are distributed world wide, are the primary cause of cryptococcosis, a life threatening disease. the study of environmental and clinical isolates of cryptococcosis is an important contribution to the epidemiology and ecology of the fungus. the aim of this work was to determine the presence of c. neoformans and c. gattii in the environment in bogotá, colombia's capital city and to establish the relation be ...201627706379
cryptococcal osteomyelitis of the skull in a liver transplant patient.cryptococcus neoformans is an opportunistic fungal pathogen and an important cause of morbidity and mortality in immunocompromised patients. we report a case of osteomyelitis caused by c. neoformans in a liver transplant recipient who presented with a headache and scalp lump after sustaining mild head trauma. there was no evidence of central nervous system involvement or dissemination. this is the first known case report of isolated cryptococcal osteomyelitis in a liver transplant recipient.201627601128
targeted genome editing via crispr in the pathogen cryptococcus neoformans.low rates of homologous integration have hindered molecular genetic studies in cryptococcus neoformans over the past 20 years, and new tools that facilitate genome manipulation in this important pathogen are greatly needed. to this end, we have investigated the use of a class 2 crispr system in c. neoformans (formerly c. neoformans var. grubii). we first expressed a derivative of the streptococcus pyogenes cas9 nuclease in c. neoformans, and showed that it has no effect on growth, production of ...201627711143
pulmonary cryptococcosis in the immunocompetent patient-many questions, some answers.background.  there are no prospective data regarding the management of pulmonary cryptococcosis in the immunocompetent patient. clinical guidelines recommend oral fluconazole for patients with mild to moderate symptoms and amphotericin b plus flucytosine followed by fluconazole for severe disease. it is unclear whether patients who have histological evidence of cryptococcus neoformans but negative cultures will even respond to drug treatment. we evaluated and managed a patient whose presentation ...201627704021
erratum to: transcriptional control of sexual development in cryptococcus neoformans. 201627687233
antifungal susceptibility testing and genotyping characterization of cryptococcus neoformans and gattii isolates from hiv-infected patients of ribeirão preto, são paulo, brazil.cryptococcosis is a leading invasive fungal infection in immunocompromised patients. considering the high prevalence and severity of these infections in immunocompromised patients attended at hc-fmrp-usp, the present research aimed to characterize the clinical isolates of cryptococcus strains by biochemical and molecular methods and evaluate antifungal susceptibility of clinical isolates. fifty isolates from 32 hiv-positive patients were obtained at hc-fmrp-usp. most of the isolates (78.1%) were ...201627680174
systematic functional analysis of kinases in the fungal pathogen cryptococcus neoformans.cryptococcus neoformans is the leading cause of death by fungal meningoencephalitis; however, treatment options remain limited. here we report the construction of 264 signature-tagged gene-deletion strains for 129 putative kinases, and examine their phenotypic traits under 30 distinct in vitro growth conditions and in two different hosts (insect larvae and mice). clustering analysis of in vitro phenotypic traits indicates that several of these kinases have roles in known signalling pathways, and ...201627677328
activity of vt-1129 against cryptococcus neoformans clinical isolates with high fluconazole mics.although antifungal drug resistance in the human fungal pathogen cryptococcus neoformans is relatively uncommon, fluconazole-resistant strains are problematic for preemptive treatment of cryptococcal antigenemia or during cryptococcal meningitis consolidation therapy. we analyzed activity of the experimental antifungal vt-1129 on 51 clinical cryptococcus neoformans isolates previously screened for fluconazole resistance; with an emphasis on fluconazole dose-dependent (mic 16-32 μg/ml) or resista ...201627664991
synergistic effect of pedalitin and amphotericin b against cryptococcus neoformans by in vitro and in vivo evaluation.cryptococcosis is an opportunistic fungal infection responsible for high morbidity and mortality in immunocompromised patients. combination of antifungal substances is a promising way to increase the percentage of successful treatment. pedalitin (ped) is a natural substance obtained from pterogyne nitens. the aim of this study was to verify the efficacy of ped alone and in combination with amphotericin b (amb) in vitro and in vivo against cryptococcus spp. in the in vitro assay, minimum inhibito ...201627742203
new weapons in the cryptococcus infection toolkit.the global burden of fungal infections is unacceptably high. the human fungal pathogen cryptococcus neoformans causes cryptococcosis and accounts for a significant proportion of this burden. cryptococci undergo a number of elaborate interactions with their hosts, including survival and proliferation within phagocytes as well as dissemination to the central nervous system and other tissues. in this review we highlight a number of exciting recent advances in the field of cryptococcal biology. in p ...201627522351
inhibition of the calcineurin pathway by two flavonoids isolated from miliusa sinensis finet & gagnep.in order to discover plant-derived signaling pathway inhibitors with antifungal properties, a two-component screening system utilizing the calcineurin and hog1 mitogen-activated protein kinase pathways responsible for the virulence networks of cryptococcus neoformans was employed, owing to the counter-regulatory actions of these pathways. of the 1,000 plant extracts tested, two bioactive compounds from miliusa sinensis were found to act specifically on the calcineurin pathway of c. neoformans. t ...201627363478
pattern, clinical characteristics, and outcome of meningitis among hiv-infected adults admitted in a tertiary hospital in north western tanzania: a cross-sectional study.background. limited information exists on the etiologies, clinical characteristics, and outcomes of meningitis among hiv-infected patients in africa. we conducted a study to determine the etiology, clinical characteristics, and outcomes of meningitis among hiv-infected adults. methods. a prospective cross-sectional hospital based study was conducted among hiv-infected patients aged ≥18 years admitted to the medical wards with symptoms and signs of meningitis. sociodemographic and clinical inform ...201627651801
genetic and environmental influences on the germination of basidiospores in the cryptococcus neoformans species complex.in basidiomycetous fungi, the viability of basidiospores is an important component of sexual fitness. however, relatively little is known about the genetic and environmental factors influencing basidiospore germination. in this study, we used human opportunistic yeast pathogens, cryptococcus neoformans and cryptococcus deneoformans, as models to investigate the potential effects of selected genetic and environmental factors on basidiospore germination. a total of five strains with known genome s ...201627644692
chemical inhibitors of non-homologous end joining increase targeted construct integration in cryptococcus neoformans.the development of a biolistic transformation protocol for cryptococcus neoformans over 25 years ago ushered in a new era of molecular characterization of virulence in this previously intractable fungal pathogen. however, due to the low rate of homologous recombination in this species, the process of creating targeted gene deletions using biolistic transformation remains inefficient. to overcome the corresponding difficulty achieving molecular genetic modifications, members of the cryptococcus c ...201627643854
comparison of bact/alert fan and fan plus bottles with conventional medium for culturing cerebrospinal fluid.we compared the bact/alert system fan and fan plus media to conventional media for culturing cerebrospinal fluid (csf) with 2,545 samples. fan/fan plus bottles showed better performance for isolating microorganisms in csf than conventional media (positive rate, 7.2% [182/2,545] versus 3.1% [80/2,545]). the incremental recovery rate of cryptococcus neoformans from fan plus bottles was higher than that from fan bottles.201627629894
unique roles of the unfolded protein response pathway in fungal development and differentiation.cryptococcus neoformans, a global fungal meningitis pathogen, employs the unfolded protein response pathway. this pathway, which consists of an evolutionarily conserved ire1 kinase/endoribonuclease and a unique transcription factor (hxl1), modulates the endoplasmic reticulum stress response and pathogenicity. here, we report that the unfolded protein response pathway governs sexual and unisexual differentiation of c. neoformans in an ire1-dependent but hxl1-independent manner. the ire1∆ mutants ...201627629591
cryptococcal cellulitis on the shin of an immunosuppressed patient.cryptococcus neoformans is a common fungus found throughout the environment that causes opportunistic disease in immunocompromised individuals. infection of humans with c neoformans usually manifests as lung disease through inhalation of spores or meningoencephalitis by involvement of the central nervous system. rarely, dissemination in the form of cutaneous lesions can occur in individuals with long term immunosuppression. we present a patient with c. neoformans manifesting as cellulitis with f ...201627617599
calcineurin targets involved in stress survival and fungal virulence.calcineurin governs stress survival, sexual differentiation, and virulence of the human fungal pathogen cryptococcus neoformans. calcineurin is activated by increased ca2+ levels caused by stress, and transduces signals by dephosphorylating protein substrates. herein, we identified and characterized calcineurin substrates in c. neoformans by employing phosphoproteomic tio2 enrichment and quantitative mass spectrometry. the identified targets include the transactivator crz1 as well as novel subst ...201627611567
in vitro antifungal susceptibility profiles of cryptococcus species isolated from hiv-associated cryptococcal meningitis patients in zimbabwe.cryptococcus neoformans is the leading cause of cryptococcosis in hiv-infected subjects worldwide. treatment of cryptococcosis is based on amphotericin b, flucytosine, and fluconazole. in zimbabwe, little is known about antifungal susceptibility of cryptococcus. sixty-eight genotyped cryptococcus isolates were tested for antifungal profiles. amphotericin b, isavuconazole, and voriconazole showed higher activity than other triazoles. fluconazole and flucytosine were less effective, with geometric ...201627608538
lung epithelium is the major source of il-33 and is regulated by il-33-dependent and il-33-independent mechanisms in pulmonary cryptococcosis.inhalation of the fungus cryptococcus neoformans (c. neoformans) results in pulmonary cryptococcosis associated with il-33-dependent type 2 immunity. lung epithelium represents the initial contact site of infection. the role of il-33 in type 2 immunity has been analyzed, but the source of this cytokine and its effect on lung epithelial cell function in pulmonary cryptococcosis remained unclear. in mice infected with c. neoformans, we identified alveolar type 2 epithelial cells as major source of ...201627596810
cryptococcal meningitis complicating sarcoidosis.cryptococcal meningitis is an uncommon but severe complication of sarcoidosis.201627583871
a small protein associated with fungal energy metabolism affects the virulence of cryptococcus neoformans in mammals.the pathogenic yeast cryptococcus neoformans causes cryptococcosis, a life-threatening fungal disease. c. neoformans has multiple virulence mechanisms that are non-host specific, induce damage and interfere with immune clearance. microarray analysis of c. neoformans strains serially passaged in mice associated a small gene (cnag_02591) with virulence. this gene, hereafter identified as hva1 (hypervirulence-associated protein 1), encodes a protein that has homologs of unknown function in plant an ...201627583447
glutathione may have implications in the design of 3-bromopyruvate treatment protocols for both fungal and algal infections as well as multiple myeloma.in different fungal and algal species, the intracellular concentration of reduced glutathione (gsh) correlates closely with their susceptibility to killing by the small molecule alkylating agent 3-bromopyruvate (3bp). additionally, in the case of cryptococcus neoformans cells 3bp exhibits a synergistic effect with buthionine sulfoximine (bso), a known gsh depletion agent. this effect was observed when 3bp and bso were used together at concentrations respectively of 4-5 and almost 8 times lower t ...201627582536
identification of disseminated cryptococcosis using maldi-tof ms and clinical evaluation.disseminated cryptococcosis is rare but can often become severe with a poor outcome. given recent reports that matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (maldi-tof ms) analyser is useful for cryptococcus species identification, it was applied retrospectively to past cases of disseminated cryptococcosis at our hospital over the past 10 years, and their clinical courses were reviewed. for each case, the retained cryptococcus spp. were used for identification usin ...201627581774
localized cutaneous cryptococcosis: summary of reported cases in japan.a 68-year-old male plasterer with no history of trauma presented to our clinic in march 2012 with a 16×14-mm ulcer that developed following a crushed small papule on the right anterior chest. in april 2012, the patient was referred to another hospital, where cutaneous cryptococcosis was diagnosed based on discharge culture results. the patient was treated with oral itraconazole at a dose of 150 mg/day for 10 weeks; however, the ulcer remained unchanged and he discontinued the treatment. in may 2 ...201627581773
intron retention-dependent gene regulation in cryptococcus neoformans.the biological impact of alternative splicing is poorly understood in fungi, although recent studies have shown that these microorganisms are usually intron-rich. in this study, we re-annotated the genome of c. neoformans var. neoformans using rna-seq data. comparison with c. neoformans var. grubii revealed that more than 99% of orf-introns are in the same exact position in the two varieties whereas utr-introns are much less evolutionary conserved. we also confirmed that alternative splicing is ...201627577684
mechanisms by which interleukin-12 corrects defective nk cell anticryptococcal activity in hiv-infected patients.cryptococcus neoformans is a pathogenic yeast and a leading cause of life-threatening meningitis in aids patients. natural killer (nk) cells are important immune effector cells that directly recognize and kill c. neoformans via a perforin-dependent cytotoxic mechanism. we previously showed that nk cells from hiv-infected patients have aberrant anticryptococcal killing and that interleukin-12 (il-12) restores the activity at least partially through restoration of nkp30. however, the mechanisms ca ...201627555306
novel cell-based in vitro screen to identify small-molecule inhibitors against intracellular replication of cryptococcus neoformans in macrophages.the fungal pathogen cryptococcus neoformans poses a major threat to immunocompromised patients and is a leading killer of human immunodeficiency virus (hiv)-infected patients worldwide. cryptococci are known to manipulate host macrophages and can either remain latent or proliferate intracellularly within the host phagocyte, a favourable niche that also renders them relatively insensitive to antifungal agents. here we report an attempt to address this limitation by using a fluorescence-based drug ...201627289450
fragment-based whole cell screen delivers hits against m. tuberculosis and non-tuberculous mycobacteria.reactive multi-target 'fragment drugs' represent critical components of current tuberculosis regimens. these compounds, such as pyrazinamide, are old synthetic antimycobacterials that are activated inside mycobacterium tuberculosis bacilli and are smaller than the usual drug-like, single-target molecules. based on the success of small 'dirty' drugs in the chemotherapy of tuberculosis, we suggested previously that fragment-based whole cell screens should be introduced in our current antimycobacte ...201627656168
infection in southern chinese patients with systemic lupus erythematosus: spectrum, drug resistance, outcomes, and risk factors.to investigate the spectrum, antibiotic-resistant pattern, risk factors, and outcomes of infection in patients hospitalized with systemic lupus erythematosus (sle).201627307524
infectious cause of death determination using minimally invasive autopsies in developing countries.in developing countries, the knowledge of the microorganisms causing fatal infections is critical and could help designing and implementing more effective preventive interventions and treatment guidelines. we aimed to develop and validate protocols for microbiological analysis in post-mortem samples obtained during minimally invasive autopsy (mia) procedures and to assess their performance. thirty mias performed in adults at maputo central hospital in southern mozambique were included in the ana ...201626508103
new structural insights into golgi reassembly and stacking protein (grasp) in solution.among all proteins localized in the golgi apparatus, a two-pdz (psd95/dlga/zo-1) domain protein plays an important role in the assembly of the cisternae. this golgi reassembly and stacking protein (grasp) has puzzled researchers due to its large array of functions and relevance in golgi functionality. we report here a biochemical and biophysical study of the grasp55/65 homologue in cryptococcus neoformans (cngrasp). bioinformatic analysis, static fluorescence and circular dichroism spectroscopie ...201627436376
illuminating uveitis: metagenomic deep sequencing identifies common and rare pathogens.ocular infections remain a major cause of blindness and morbidity worldwide. while prognosis is dependent on the timing and accuracy of diagnosis, the etiology remains elusive in ~50 % of presumed infectious uveitis cases. the objective of this study is to determine if unbiased metagenomic deep sequencing (mds) can accurately detect pathogens in intraocular fluid samples of patients with uveitis.201627562436
experience with splenic abscess from southern india.splenic abscess is a rare entity with potentially life threatening complications. sparse recent published data are available documenting the aetiological profile and management of patients with splenic abscess from india.201627891372
isolation of conditional mutations in genes essential for viability of cryptococcus neoformans.discovering the genes underlying fundamental processes that enable cells to live and reproduce is a technical challenge, because loss of gene function in mutants results in organisms that cannot survive. this study describes a forward genetics method to identify essential genes in fungi, based on the propensity for agrobacterium tumefaciens to insert t-dna molecules into the promoters or 5' untranslated regions of genes and by placing a conditional promoter within the t-dna. insertions of the pr ...201627783209
sandpits as a reservoir of potentially pathogenic fungi for children.fungi belonging to various physiological and morphological groups present in the environment are potential human pathogens. some of them are considered as emerging pathogens. therefore, their presence in children's playgrounds should be regarded as health risk factor.201628030920
genetic and phenotypic analyses of calcineurin a subunit in arthroderma vanbreuseghemii.calcineurin is a serine/threonine protein phosphatase that consists of catalytic (calcineurin a) and regulatory (calcineurin b) subunits. the conserved protein plays important roles in various biological processes. drug combination of fluconazole and the calcineurin inhibitor (fk506) showed synergistic effects against dermatophytes. in the current study, we identified the calcineurin a homologous gene (tmcana) in the dermatophyte arthroderma vanbreuseghemii (anamorph: trichophyton mentagrophytes ...201626483437
role of pathogen-associated molecular patterns (pamps) in immune responses to fungal infections.recent years have seen the rise of invasive fungal infections, which are mostly due to the increase in patients. three major opportunistic fungal species in human are aspergillus fumigatus, candida albicans, and cryptococcus neoformans that pose the biggest concern for these immunocompromised patients' mortality. the growing occurrence of opportunistic fungal infections has sparked the interest to understand defense mechanisms against pathogenic fungi. toll-like receptors (tlrs), as a part of in ...201627851904
transcriptional control of drug resistance, virulence and immune system evasion in pathogenic fungi: a cross-species comparison.transcription factors are key players in the control of the activation or repression of gene expression programs in response to environmental stimuli. the study of regulatory networks taking place in fungal pathogens is a promising research topic that can help in the fight against these pathogens by targeting specific fungal pathways as a whole, instead of targeting more specific effectors of virulence or drug resistance. this review is focused on the analysis of regulatory networks playing a ce ...201627812511
antifungal drugs: the current armamentarium and development of new agents.invasive fungal infections are becoming an increasingly important cause of human mortality and morbidity, particularly for immunocompromised populations. the fungal pathogens candida albicans, cryptococcus neoformans, and aspergillus fumigatus collectively contribute to over 1 million human deaths annually. hence, the importance of safe and effective antifungal therapeutics for the practice of modern medicine has never been greater. given that fungi are eukaryotes like their human host, the numb ...201627763259
antifungal activity of plasmacytoid dendritic cells against cryptococcus neoformans in vitro requires expression of dectin-3 (clec4d) and reactive oxygen species.conventional dendritic cells (cdcs) are critical for protection against pulmonary infection with the opportunistic fungal pathogen cryptococcus neoformans; however, the role of plasmacytoid dendritic cells (pdcs) is unknown. we show for the first time that murine pdcs have direct activity against c. neoformans via reactive oxygen species (ros), a mechanism different from that employed to control aspergillus fumigatus infections. the anticryptococcal activity of murine pdcs is independent of opso ...201627324480
candidacidal activity of selected ceragenins and human cathelicidin ll-37 in experimental settings mimicking infection sites.fungal infections, especially those caused by antibiotic resistant pathogens, have become a serious public health problem due to the growing number of immunocompromised patients, including those subjected to anticancer treatment or suffering from hiv infection. in this study we assessed fungicidal activity of the ceragenins csa-13, csa-131 and csa-192 against four fluconazole-resistant candida strains. we found that ceragenins activity against planktonic candida cells was higher than activity of ...201627315208
antimicrobial activity of new 2-thioxo-benzo[g]quinazolin-4(3h)-one derivatives.the antimicrobial activity of a synthesized series of 28 2-thioxo-benzo[g]quinazolin-4(3h)-one derivatives was evaluated in vitro against five gram-positive bacteria, including bacillus subtilis, enterococcus faecalis, staphylococcus aureus, staphylococcus epidermidis and streptococcus pyogenes. the antibacterial activity was extended to include five gram-negative bacteria: pseudomonas aeruginosa, escherichia coli, proteus mirabilis, klebsiella oxytoca and enterobacter cloacae. furthermore, the ...201627306606
the extracellular matrix of fungal biofilms.a key feature of biofilms is their production of an extracellular matrix. this material covers the biofilm cells, providing a protective barrier to the surrounding environment. during an infection setting, this can include such offenses as host cells and products of the immune system as well as drugs used for treatment. studies over the past two decades have revealed the matrix from different biofilm species to be as diverse as the microbes themselves. this chapter will review the composition an ...201627271680
ultrasound- and molecular sieves-assisted synthesis, molecular docking and antifungal evaluation of 5-(4-(benzyloxy)-substituted phenyl)-3-((phenylamino)methyl)-1,3,4-oxadiazole-2(3h)-thiones.a novel series of 5-(4-(benzyloxy)substituted phenyl)-3-((phenyl amino)methyl)-1,3,4-oxadiazole-2(3h)-thione mannich bases 6a-o were synthesized in good yield from the key compound 5-(4-(benzyloxy)phenyl)-1,3,4-oxadiazole-2(3h)-thione by aminomethylation with paraformaldehyde and substituted amines using molecular sieves and sonication as green chemistry tools. the antifungal activity of the new products was evaluated against seven human pathogenic fungal strains, namely, candida albicans atcc 2 ...201627171073
cell wall integrity signalling in human pathogenic fungi.fungi are surrounded by a rigid structure, the fungal cell wall. its plasticity and composition depend on active regulation of the underlying biosynthesis and restructuring processes. this involves specialised signalling pathways that control gene expression and activities of biosynthetic enzymes. the cell wall integrity (cwi) pathway is the central signalling cascade required for the adaptation to a wide spectrum of cell wall perturbing conditions, including heat, oxidative stress and antifunga ...201627155139
antimicrobial activity of synthesized 2-methylthiobenzo[g][1,2,4]- triazolo[1,5-a]quinazoline derivatives.the present study was carried out to evaluate the antimicrobial activity of a synthesized 2-methylthio-benzo[g][1,2,4]triazolo[1,5- a]quinazoline series. the compounds (1-21) were tested against a variety of gram-positive bacterial species including bacillus subtilis (rcmb 01001 69-3), enterococcus faecalis (rcmb 0100154-2), staphylococcus aureus (rcmb 0100183-9), staphylococcus epidermidis (rcmb 0100183-9) and streptococcus pyogenes (rcmb 0100172-5). in addition, gram-negative bacteria were als ...201627140181
antifungal susceptibility patterns of a global collection of fungal isolates: results of the sentry antifungal surveillance program (2013).among 1846 fungal clinical isolates from 31 countries, echinocandin resistance in candida spp. ranged from 0.0% to 2.8% (highest for anidulafungin versus candida glabrata), and fluconazole resistance was noted among 11.9% and 11.6% of the c. glabrata and candida tropicalis, respectively. two isolates of aspergillus fumigatus displayed elevated mics for itraconazole and carried cyp51a mutations encoding tr34 l98h. all cryptococcus neoformans had azole mic values below epidemiological cutoff value ...201627061369
synthesis of newer 1,2,3-triazole linked chalcone and flavone hybrid compounds and evaluation of their antimicrobial and cytotoxic activities.the present study was carried out in an attempt to synthesize a new class of antimicrobial and antiplasmodial agents by copper catalyzed click chemistry to afford 25 compounds 10-14(a-e) of 1,4-disubstituted-1,2,3-triazole derivatives of chalcones and flavones. the structures of the newly synthesized compounds were established by elemental analysis, ir, (1)h nmr, (13)c nmr and mass spectral data. the newly synthesized compounds were evaluated for their antibacterial activity against gram positiv ...201626922227
human fungal pathogens: why should we learn?human fungal pathogens that cause invasive infections are hidden killers, taking lives of one and a half million people every year. however, research progress in this field has not been rapid enough to effectively prevent or treat life-threatening fungal diseases. to update recent research progress and promote more active research in the field of human fungal pathogens, eleven review articles concerning the virulence mechanisms and host interactions of four major human fungal pathogens-candida a ...201626920875
a novel inhibition elisa for the detection and monitoring of penicillium marneffei antigen in human serum.the thermally dimorphic fungus penicillium marneffei is a causative agent of penicilliosis marneffei, a disease considered to be an acquired immune deficiency syndrome (aids)-defining illness in southeast asia and southern china. we have developed an inhibition enzyme-linked immunosorbent assay (inh-elisa) incorporating the yeast phase specific mannoprotein-binding monoclonal antibody 4d1 for the detection of p. marneffei infection. in our sample set, the test detected antigenemia in all 45 (100 ...201626838686
aspergillus fumigatus cap59-like protein a is involved in α1,3-mannosylation of gpi-anchors.glycosylphosphatidylinositol (gpi) attaches a variety of eukaryotic proteins to the outer leaflet of the plasma membrane. in fungi, these proteins may also be transferred to the cell wall, to which they are covalently linked via a remnant of the gpi-anchor. they play crucial physiological roles in cell-cell interactions, adhesion or cell wall biogenesis. the biosynthesis of gpi-anchors in the endoplasmic reticulum, their transfer to proteins, early remodelling and transport to the golgi apparatu ...201626369907
pathogen gene expression profiling during infection using a nanostring ncounter platform.nanostring ncounter is a recently developed platform that can make direct multiplexed measurement of gene expression using color-coded probe pairs (geiss et al., nat biotechnol 26(3):317-325, 2008; malkov et al., bmc res notes 2:80, 2009). we have found that this platform is uniquely suitable for quantification of pathogen gene expression during infection, where pathogen rna comprises a tiny portion of total rna isolated from the infected tissue. here, we describe a protocol that we have success ...201626483015
expression and characterization of a talaromyces marneffei active phospholipase b expressed in a pichia pastoris expression system.phospholipase b is a virulence factor for several clinically important pathogenic fungi, including candida albicans, cryptococcus neoformans and aspergillus fumigatus, but its role in the thermally dimorphic fungus talaromyces marneffei remains unclear. here, we provide the first report of the expression of a novel phospholipase gene, designated tmplb1, from t. marneffei in the eukaryotic expression system of pichia pastoris gs115. sensitive real-time quantitative reverse-transcription pcr (qrt- ...201627876784
nimesulide inhibits pathogenic fungi: pge2-dependent mechanisms.certain non-steroidal anti-inflammatory drugs can inhibit fungal growth, fungal prostaglandin e2 production, and enzyme activation. this study aims to investigate the antifungal effect of nimesulide against pathogenic filamentous fungi and yeast. the experiments detailed below were also designed to investigate whether the action is dependent on e2 fungal prostaglandins. our data showed that nimesulide exhibited potent antifungal activity, mainly against trichophyton mentagrophytes (atcc 9533) an ...201727866353
central role of the trehalose biosynthesis pathway in the pathogenesis of human fungal infections: opportunities and challenges for therapeutic development.invasive fungal infections cause significant morbidity and mortality in part due to a limited antifungal drug arsenal. one therapeutic challenge faced by clinicians is the significant host toxicity associated with antifungal drugs. another challenge is the fungistatic mechanism of action of some drugs. consequently, the identification of fungus-specific drug targets essential for fitness in vivo remains a significant goal of medical mycology research. the trehalose biosynthetic pathway is found ...201728298477
in vitro and in vivo antifungal profile of a novel and long acting inhaled azole, pc945, on aspergillus fumigatus infection.the profile of pc945, a novel triazole antifungal, designed for administration via inhalation, has been assessed in a range of in vitro and in vivo studies. pc945 was characterized as a potent, tight-binding inhibitor of aspergillus fumigatus sterol 14α-demethylase (cyp51a and cyp51b) activity (ic50, 0.23 μm and 0.22 μm, respectively), with characteristic type ii azole binding spectra. against 96 clinically isolated a. fumigatus strains, the mic values of pc945 ranged from 0.032∼>8 μg/ml, whilst ...201728223388
iron acquisition in fungal pathogens of humans.the devastating infections that fungal pathogens cause in humans are underappreciated relative to viral, bacterial and parasitic diseases. in recent years, the contributions to virulence of reductive iron uptake, siderophore-mediated uptake and heme acquisition have been identified in the best studied and most life-threatening fungal pathogens: candida albicans, cryptococcus neoformans and aspergillus fumigatus. in particular, exciting new work illustrates the importance of iron acquisition from ...201728217776
ram1 gene, encoding a subunit of farnesyltransferase, contributes to growth, antifungal susceptibility to amphotericin b of aspergillus fumigatus. 201728159997
broad spectrum anti-infective properties of benzisothiazolones and the parallels in their anti-bacterial and anti-fungal effects.various mono- and bis-benzisothiazolone derivatives were synthesized and screened against different strains of bacteria and fungi in order to understand the effect of multiple electrophilic sulfur atoms and substitution pattern in the immediate vicinity of reactive sulfur. staphyllococcus aureus-atcc 7000699, mrsa and s. aureus-atcc 29213 (quality control strain) were more susceptible to this class of compounds, and the most potent derivative 1.15 had mic50 of 0.4μg/ml (cf. gentamicin=0.78μg/ml) ...201728159413
activity of a long-acting echinocandin (cd101) and seven comparator antifungal agents tested against a global collection of contemporary invasive fungal isolates in the sentry 2014 antifungal surveillance program.the activity of cd101 and comparator antifungal agents against 606 invasive fungal isolates collected worldwide during 2014 was evaluated using the clinical and laboratory standards institute (clsi) method. all candida albicans (n = 251), candida tropicalis (n = 51), candida krusei (n = 16), and candida dubliniensis (n = 11) isolates were inhibited by ≤0.12 μg/ml of cd101 and were susceptible or showed wild-type susceptibility to the other echinocandins tested. five c. glabrata isolates (n = 100 ...201728052853
highly efficient transformation system for malassezia furfur and malassezia pachydermatis using agrobacterium tumefaciens-mediated transformation.malassezia spp. are part of the normal human and animal mycobiota but are also associated with a variety of dermatological diseases. the absence of a transformation system hampered studies to reveal mechanisms underlying the switch from the non-pathogenic to pathogenic life style. here we describe, a highly efficient agrobacterium-mediated genetic transformation system for malassezia furfur and m. pachydermatis. a binary t-dna vector with the hygromycin b phosphotransferase (hpt) selection marke ...201728064034
cysteinyl leukotrienes as novel host factors facilitating cryptococcus neoformans penetration into the brain.cryptococcus neoformas infection of the central nervous system (cns) continues to be an important cause of mortality and morbidity, and a major contributing factor is our incomplete knowledge of the pathogenesis of this disease. here, we provide the first direct evidence that c. neoformans exploits host cysteinyl leukotrienes (lts), formed via lt biosynthetic pathways involving cytosolic phospholipase a2 α (cpla2 α) and 5-lipoxygenase (5-lo) and acting via cysteinyl leukotriene type 1 receptor ( ...201727573789
geographic distribution of patients affected by cryptococcus neoformans/cryptococcus gattii species complexes meningitis, pigeon and tree populations in southern brazil.cryptococcal meningitis is mainly caused by members of the c. neoformans/c. gattii species complexes. the ecological niches of cryptococcus species have extensively been studied, but its epidemiological relationship with meningitis cases is still unknown. in this study, we estimate the relationship between cryptococcal meningitis cases and tree and pigeon populations, the classical niches of members of c. neoformans/c. gattii sensu lato. we analysed the records of every patient whose cerebrospin ...201727561904
endoscopic ultrasound fine-needle aspiration diagnosis of cryptococcus neoformans. 201727639329
cryptococcosis mimicking lung carcinoma with brain metastases in an immunocompetent patient.cryptococcosis is a fungal infection caused by cryptococcus spp. that enters the body via inhalation. this ubiquitous yeast has gained notoriety as an opportunistic pathogen in the immunosuppressed population. the authors report a case of a previously-well adult male presented with left-sided weakness. imaging demonstrated a pulmonary mass and 2 contrast-enhancing intracranial lesions-all features suggestive of a primary lung carcinoma with brain metastases. however, further investigations confi ...201727769644
infections of the central nervous system after unrelated donor umbilical cord blood transplantation or human leukocyte antigen-matched sibling transplantation.we analyzed the incidence, clinical characteristics, prognostic factors, and outcome of central nervous system (cns) infections in consecutive patients with receiving umbilical cord blood transplantation (ucbt) (n = 343) or hla-matched sibling donor stem cell transplantation (mst) (n = 366). thirty-four cns infections were documented at a median time of 116 days after transplantation (range, 7 to 1161). the cumulative incidence (ci) risk of developing a cns infection was .6% at day +30, 2.3% at ...201727794456
equine pulmonary cryptococcosis: a comparative literature review and evaluation of fluconazole monotherapy.cryptococcus is the most common fungal respiratory pathogen in australian horses, manifesting primarily as pulmonary granulomas. disease severity at presentation is dependent on the athletic use of the horse. the diagnosis and estimation of disease severity are centred around clinical findings, cytological evaluation of respiratory tract secretions, diagnostic imaging, and antigen titre testing. both the lateral flow assay and the latex cryptococcal antigen titre are used, and important similari ...201727655152
pulsed dye laser treatment of primary cryptococcal laryngitis: a novel approach to an uncommon disease.an 82-year-old supplemental oxygen dependent woman with severe copd presented with an eight month history of worsening hoarseness and stridor. office laryngoscopy revealed laryngeal edema and ulcerative masses throughout the larynx. in-office biopsies were positive for cryptococcus neoformans. this report details a novel approach to the treatment of cryptococcal laryngitis, a combination of in-office pulsed-dye laser (pdl) ablation and medical therapy. despite treatment with oral fluconazole, th ...201727654751
molecular characterization of adenylyl cyclase complex proteins using versatile protein-tagging plasmid systems in cryptococcus neoformans.in this study, we aimed to generate a series of versatile tagging plasmids that can be used in diverse molecular biological studies of the fungal pathogen cryptococcus neoformans. we constructed 12 plasmids that can be used to tag a protein of interest with a gfp, mcherry, 4×flag, or 6×ha, along with nourseothricin-, neomycin-, or hygromycin-resistant selection markers. using this tagging plasmid set, we explored the adenylyl cyclase complex (acc), consisting of adenylyl cyclase (cac1) and its a ...201727780958
invasive granulomatous cryptococcal sinusitis in an adult with multiple myeloma.we report a case of cryptococcal sinusitis, a rare presentation of cryptococcus neoformans infection in a patient with multiple myeloma. the objective of this case report is to highlight the utility of structural and functional imaging modalities in the differential diagnosis of sinonasal soft tissue masses in the immunocompromised patient population. pet-ct was the first imaging modality in this patient, who presented for routine follow-up staging of multiple myeloma, and was asymptomatic at th ...201727816878
using flow cytometry to analyze cryptococcus infection of macrophages.flow cytometry is a powerful analytical technique, which is increasingly being used to study the interaction between host cells and intracellular pathogens. flow cytometry is capable of measuring a greater number of infected cells within a sample compared to alternative techniques such as fluorescence microscopy. this means that robust quantification of rare events during infection is possible. our lab and others have developed flow cytometry methods to study interactions between host cells and ...201727815892
a monoclonal antibody to cryptococcus neoformans glucuronoxylomannan manifests hydrolytic activity for both peptides and polysaccharides.studies in the 1980s first showed that some natural antibodies were "catalytic" and able to hydrolyze peptide or phosphodiester bonds in antigens. many naturally occurring catalytic antibodies have since been isolated from human sera and associated with positive and negative outcomes in autoimmune disease and infection. the function and prevalence of these antibodies, however, remain unclear. a previous study suggested that the 18b7 monoclonal antibody against glucuronoxylomannan (gxm), the majo ...201727872188
rewiring of signaling networks modulating thermotolerance in the human pathogen cryptococcus neoformans.thermotolerance is a crucial virulence attribute for human pathogens, including the fungus cryptococcus neoformans that causes fatal meningitis in humans. loss of the protein kinase sch9 increases c. neoformans thermotolerance, but its regulatory mechanism has remained unknown. here, we studied the sch9-dependent and sch9-independent signaling networks modulating c. neoformans thermotolerance by using genome-wide transcriptome analysis and reverse genetic approaches. during temperature upshift, ...201727866167
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