S. aureus is the leading cause of infective endocarditis in developed world, affecting ~40,000 individuals each year United States, and second bacteremia (D. R. Murdoch et al., Arch Intern Med 169:463–473, 2009, http://dx.doi.org/10.1001/archinternmed.2008.603 , H. Wisplinghoff Clin Infect Dis 39:309–317, 2004, http://dx.doi.org/10.1086/421946 ). Even with current medical advances, bloodstream infections carry mortality rates 20 to 66% (S. Y. Tong Microbiol Rev 28:603–661, 2015,...

Background. Staphylococcus aureus causes life-threatening infections, including infective endocarditis, sepsis, and pneumonia. β-toxin is a sphingomyelinase encoded for by virtually all S. strains exhibits human immune cell cytotoxicity. The toxin enhances phenol-soluble modulin activity, its activity enhanced superantigens. bacteriophage φSa3 inserts into the gene in strains, inactivating it majority of clonal groups. Hence, most are reported not to secrete β-toxin. Methods. This dynamic...

A likely contributor to the increased incidence of non- albicans candidemias involving Candida glabrata is ease with which this yeast acquires azole resistance, in large part due induction ATP-binding cassette transporter-encoding gene CDR1 . Azole drugs lead Pdr1 transactivation, a central model being that factor binds these directly. Here we provide evidence activated without by use genetic means inhibit expression drug target-encoding ERG11 These acute reductions Erg11 levels elevated...

Excessive weight and obesity are associated with the development of diabetes mellitus type 2 (DMII) in humans. They also pose high risks Staphylococcus aureus colonization overt infections. S. causes a wide range severe illnesses both healthy immunocompromised individuals. Among virulence factors, superantigens essential for pathogenicity. In this study, we show that rabbits chronically exposed to superantigen toxic shock syndrome toxin-1 (TSST-1) experience impaired glucose tolerance,...

The most commonly used antifungal drugs are the azole compounds, which interfere with biosynthesis of fungal-specific sterol: ergosterol. pathogenic yeast Candida glabrata acquires resistance to like fluconazole via mutations in a gene encoding transcription factor called PDR1. These PDR1 lead overproduction drug transporter proteins ATP-binding cassette Cdr1. In other species, mutant forms Upc2 associated resistance, owing important role this protein control expression genes enzymes...

Background Superantigens are indispensable virulence factors for Staphylococcus aureus in disease causation. stimulate massive immune cell activation, leading to toxic shock syndrome (TSS) and contributing other illnesses. However, superantigens differ their capacities induce body-wide effects. For many, production, at least as tested vitro, is not high enough reach the circulation, or proteins efficient crossing epithelial endothelial barriers, thus remaining within tissues localized on...

ABSTRACT Gram-positive bacteria cause serious human illnesses through combinations of cell surface and secreted virulence factors. We initiated studies with four these organisms to develop novel topical antibacterial agents that interfere growth exotoxin production, focusing on menaquinone analogs. Menadione, 1,4-naphthoquinone, coenzymes Q1 Q3 but not menaquinone, phylloquinone, or coenzyme Q10 inhibited the a greater extent production Staphylococcus aureus , Bacillus anthracis...

Background Human adipocytes may have significant functions in wound healing and the development of diabetes through production pro-inflammatory cytokines after stimulation by gram-negative bacterial endotoxin. Diabetic foot ulcers are most often associated with staphylococcal infections. Adipocyte responses area play a role persistence pathology. We studied effect superantigens (SAgs) on immortalized human adipocytes, alone presence endotoxin or α-toxin. Methodology/Principal Findings...

Azoles, the most commonly used antifungal drugs, specifically inhibit fungal lanosterol α-14 demethylase enzyme, which is referred to as Erg11. Inhibition of Erg11 ultimately leads a reduction in ergosterol production, an essential membrane sterol. Many Candida species, such albicans, develop mutations this enzyme reduces azole binding affinity and results increased resistance. glabrata also pathogenic yeast that has low intrinsic susceptibility drugs easily develops elevated In C. glabrata,...

Diabetic foot ulcer (DFU) infections are challenging. Staphylococcus aureus is the most commonly isolated pathogen in DFUs. Superantigens (SAgs) causative many S. infections. We hypothesized both that DFU will produce large SAg numbers, consistent with skin infections, and certain SAgs be overrepresented. assessed α-toxin profile of isolates from patients DFU, compared profiles other sources. Twenty-five were characterized. Polymerase chain reaction was used to detect genes for...

β-Toxin is an important virulence factor of Staphylococcus aureus, contributing to colonization and development disease [Salgado-Pabon, W., et al. (2014) J. Infect. Dis. 210, 784-792; Huseby, M. J., (2010) Proc. Natl. Acad. Sci. U.S.A. 107, 14407-14412; Katayama, Y., (2013) Bacteriol. 195, 1194-1203]. This cytotoxin has two distinct mechanisms action: sphingomyelinase activity DNA biofilm ligase activity. However, the mechanism that most for its role in infective endocarditis unknown. We...

Abstract Increased expression of the Candida glabrata CDR1 gene, encoding an ATP-binding cassette membrane transporter, is routinely observed in fluconazole-resistant isolates this pathogenic yeast. transcription has been well-documented to be due activity Zn2Cys6 zinc cluster-containing factor Pdr1. Gain-of-function mutations gene are most commonly cause fluconazole hyper-resistance clinical isolates. We have recently found that sterol-responsive Upc2A also acts control transcription,...

Drug-resistant microorganisms are a problem in the treatment of all infectious diseases; this is an especially acute with fungi due to existence only three major classes antifungal drugs, including azole drug fluconazole. In pathogenic yeast

ABSTRACT A variety of inducible protein degradation (IPD) systems have been developed as powerful tools for functional characterization. IPD provide a convenient mechanism rapid inactivation almost any target interest. Auxin-inducible (AID) is one the most common and has established in diverse eukaryotic research model organisms. Thus far, not use pathogenic fungal species. Here, we demonstrate that original AID second generation, AID2, work efficiently rapidly human yeasts, Candida albicans...

Candida glabrata is the second most common species causing candidiasis. C. can also readily acquire resistance to azole drugs, complicating its treatment. Here we add collection of disruption markers aid in genetic analysis this yeast. This new construct marked with a nourseothricin cassette that produces an estrogen-activated form Cre recombinase methionine-regulated manner. allows eviction and reuse facile Using marker, have constructed series strains lacking different members major...

Superantigens (SAgs) are important virulence factors in S. aureus. Recent studies identified their presence animal coagulase-negative staphylococci (CNS). The emergence of human-associated SAg+ CNS would mark a prodigious shift capabilities. We examined isolates from healthy human nares and diseased individuals, determined that no known SAgs were present.

Candida glabrata is one of the most important human fungal pathogens and has reduced susceptibility to azole-class inhibitors ergosterol biosynthesis. Although target two three classes antifungal drugs, relatively little known about regulation this critical cellular pathway.

Abstract The most commonly used antifungal drugs are the azole compounds that interfere with biosynthesis of fungal-specific sterol: ergosterol. pathogenic yeast Candida glabrata acquires resistance to like fluconazole via mutations in a gene encoding transcription factor called PDR1 . These lead overproduction drug transporter proteins ATP-binding cassette Cdr1. In other species, mutant forms Upc2 associated resistance, owing important role this protein control expression genes enzymes...

Abstract Incidences of fluconazole (FLC) resistance among Candida glabrata clinical isolates is a growing issue in clinics. The pleiotropic drug response (PDR) network C . confers azole and defined primarily by the Zn 2 Cys 6 zinc cluster-containing transcription factor Pdr1 target genes such as CDR1 , that encodes an ATP-binding cassette transporter protein thought to act FLC efflux pump. Mutations PDR1 gene render hyperactive are most common cause isolates. phenothiazine class fluphenazine...

ABSTRACT Incidences of fluconazole (FLC) resistance among Candida glabrata clinical isolates are a growing issue in clinics. The pleiotropic drug response network C. confers azole and is defined primarily by the Zn 2 Cys 6 zinc cluster-containing transcription factor Pdr1 target genes such as CDR1 , which encodes an ATP-binding cassette transporter protein thought to act FLC efflux pump. Mutations PDR1 gene that render hyperactive most common cause isolates. phenothiazine class fluphenazine...

ABSTRACT A variety of inducible protein degradation (IPD) systems have been developed as powerful tools for functional characterization. IPD provide a convenient mechanism rapid inactivation almost any target interest. Auxin-inducible (AID) is one the most common and has established in diverse eukaryotic research model organisms. Thus far, not use pathogenic fungal species. Here, we demonstrate that original AID second generation AID2 work efficiently rapidly human yeasts Candida albicans...

Abstract Fluconazole is the most commonly used antifungal today. A result of this has been inevitable selection fluconazole resistant organisms. This an especially acute problem in pathogenic yeast Candida glabrata . Elevated minimal inhibitory concentrations (MICs) for C. are frequently associated with substitution mutations within Zn2Cys6 zinc cluster-containing transcription factor-encoding gene PDR1 These mutant Pdr1 regulators drive constitutively high expression target genes like CDR1...

Abstract Azoles, the most commonly used antifungal drugs, specifically inhibit fungal lanosterol α-14 demethylase enzyme, which is referred to as Erg11. Inhibition of Erg11 ultimately leads a reduction in ergosterol production, an essential membrane sterol. Many Candida species, such albicans , develop mutations this enzyme reduces azole binding affinity and results increased resistance. glabrata also pathogenic yeast that has low intrinsic susceptibility drugs easily develops elevated These...

Abstract Two of the major classes antifungal drugs in clinical use target ergosterol biosynthesis. Despite its importance, our understanding transcriptional regulation biosynthesis genes pathogenic fungi is essentially limited to role hypoxia and sterol-stress induced transcription factors such as Upc2 Upc2A well homologs Sterol Response Element Binding (SREB) factors. To identify additional regulators Candida glabrata , an important human fungal pathogen with reduced susceptibility...