Sauergoff5646

Prevotella, Fusobacterium, and Streptococcus comprised a core mucin-degrading community across CRS subjects which generated a nutrient pool that augmented S. aureus growth on mucin as a carbon source. Finally, using RNAseq, we observed that S. aureus transcription is profoundly altered in the presence of mucin-derived metabolites, though expression of several key metabolism- and virulence-associated pathways varied between CRS-derived bacterial communities. Together, these data support a model in which S. aureus metabolism and virulence in the upper airways is dependent upon the composition of co-colonizing microbiota and the metabolites they exchange.Bordetella pertussis (Bp) is a highly contagious bacterium that is the causative agent of whooping cough (pertussis). Currently, acellular pertussis vaccines (aP; DTaP; Tdap) are used to prevent pertussis disease. However, it is clear that the aP vaccine efficacy quickly wanes, resulting in the re-emergence of pertussis. Furthermore, recent work performed by the CDC suggest that current circulating strains are genetically distinct from strains of the past. Emergence of genetically diverging strains combined with waning aP vaccine efficacy call for re-evaluation of current animal models of pertussis. In this study, we used the rat model of pertussis to compare two genetically divergent strains Tohama 1 and D420. We intranasally challenged seven-week-old Sprague-Dawley rats with 108 viable Tohama 1 and D420 and measured the hallmark signs/symptoms of Bp infection such as neutrophilia, pulmonary inflammation, and paroxysmal cough using whole body plethysmography. Onset of cough occurred between 2-4 days after Bp challenge averaging five coughs per fifteen minutes, with peak coughing occurring at day eight post infection averaging upward of thirteen coughs per fifteen minutes. However, we observed an increase of coughs in rats infected with clinical isolate D420 through 12 days post challenge. The rats exhibited increased bronchial restriction following Bp infection. Histology of the lung and flow cytometry confirm both cellular infiltration and pulmonary inflammation. D420 infection induced higher production of anti-Bp IgM antibodies compared to Tohama 1 infection. The coughing rat model provides a way of characterizing disease manifestation differences between Bp strains.Omadacycline (OMC) showed better in vitro potency than daptomycin (DAP) or vancomycin (VAN) against VanR, AMPR, DAP non-susceptible, linezolidR, cfr(B)+ Enterococcus faecium strains. In a mouse peritonitis model, OMC also showed significantly better animal survival during and at the end of the study than DAP or VAN against these E. faecium strains. However, OMC, DAP and VAN showed comparable in vitro and in vivo efficacy against a non-VRE, tetracycline-resistant, DAP-susceptible, E. faecium strain.We recently discovered that 6-thioguanine (6-TG) is an anti-virulence compound that is produced by a number of coagulase negative staphylococci. In Staphylococcus aureus, it inhibits de novo purine biosynthesis and ribosomal protein expression, thus inhibiting growth and abrogating toxin production. Mechanisms by which S. aureus may develop resistance to this compound are currently unknown. Here, we show that 6-TG-resistant S. aureus mutants emerge spontaneously when the bacteria are subjected to high concentrations of 6-TG in vitro. Whole genome sequencing of these mutants revealed frameshift and missense mutations in a xanthine-uracil permease family protein (stgP six thioguanine permease) and single nucleotide polymorphisms in hypoxanthine phosphoribosyltransferase (hpt). These mutations engender S. aureus the ability to resist both the growth inhibitory and toxin down regulation effects of 6-TG. While prophylactic administration of 6-TG ameliorates necrotic lesions in subcutaneous infection of mice with MRSA strain USA300-LAC, the drug did not reduce lesion size formed by the 6-TG resistant strains. These findings identify mechanisms of 6-TG resistance and this information can be leveraged to inform strategies to slow the evolution of resistance.Remdesivir (RDV; GS-5734; Veklury®), the first FDA-approved antiviral to treat COVID-19, is a single diastereomer monophosphoramidate prodrug of an adenosine analogue. RDV is taken up in the target cells and metabolized in multiple steps to form the active nucleoside triphosphate (TP) (GS-443902), which in turn acts as a potent and selective inhibitor of multiple viral RNA polymerases. In this report, we profiled the key enzymes involved in the RDV metabolic pathway with multiple parallel approaches (1) bioinformatic analysis of nucleoside/tide metabolic enzyme mRNA expression using public human tissue and lung single-cell RNAseq datasets; (2) protein and mRNA quantification of enzymes in human lung tissue and primary lung cells; (3) biochemical studies on the catalytic rate of key enzymes; (4) effects of specific enzyme inhibitors on the GS-443902 formation; and (5) the effects of these inhibitors on RDV antiviral activity against SARS-CoV-2 in cell culture. Our data collectively demonstrated that carboxylesterase 1 (CES1) and cathepsin A (CatA) are enzymes involved in hydrolyzing RDV to its alanine intermediate Met X, which is further hydrolyzed to the monophosphate form by histidine triad nucleotide-binding protein 1 (HINT1). The monophosphate is then consecutively phosphorylated to diphosphate and triphosphate by cellular phosphotransferases. Our data support the hypothesis that the unique properties of RDV prodrug not only allow lung-specific accumulation critical for the treatment of respiratory viral infection such as COVID-19, they also enable efficient intracellular metabolism of RDV and its Met X to monophosphate and successive phosphorylation to form the active TP in disease-relevant cells.The mechanisms underlying an in vivo switch in the resistance phenotype of P. aeruginosa after ceftazidime/avibactam treatment was investigated. The initial isolate (blood culture) was resistant to meropenem but remained susceptible to antipseudomonal cephalosporins and combinations with β-lactamase inhibitors. One week after ceftazidime/avibactam therapy, a subsequent isolate (rectal swab) recovered from the same patient showed the opposite phenotype. Whole genome sequence analysis revealed a single SNP difference between both (ST235) isolates, leading to a P162S change in a blaGES-5, creating a blaGES-15. Thus, blaGES-1, blaGES-5 and blaGES-15 were cloned and expressed in wildtype PAO1. Susceptibility profiles confirmed that the P162S substitution reverted the carbapenemase phenotype determined by the G170S change of GES-5 back into the ESBL phenotype of GES-1.Non-typical Salmonella is a primary cause of food-borne diseases and considered as a major public health concern worldwide(1, 2).….Liposomal amphotericin B (LAmB) is used for various fungal infections, but it is unclear which dosing weight to use in obese patients. The purpose of this study was to compare clinical outcomes of adjusted body weight (adjBW) versus total body weight (TBW) dosing of LAmB. This single-center, retrospective cohort study included patients who received LAmB for definitive therapy, whose TBW exceeded 120% of their ideal body weight (IBW). Analyses were conducted for 3 mg/kg adjBW versus TBW, and 5 mg/kg adjBW versus TBW. A total of 238 patients were included. For the 68 patients who received LAmB 3 mg/kg, there were no differences in safety or efficacy outcomes. selleckchem For the 170 patients who received LAmB 5 mg/kg, significantly more patients in the TBW group experienced the primary outcome of nephrotoxicity (57% vs. 35%, p-value 0.016), and had significantly higher rates of early discontinuation of LAmB due to toxicity (33% vs. 17%, p = 0.030). There was a trend towards increased 90-day mortality in the adjBW group (60% vs. 45%, p = 0.079); however, adjBW dosing was not associated with increased mortality in an adjusted model. Given lower rates of nephrotoxicity but a possible trend towards increased mortality, in patients whose TBW exceeds 120% of IBW, dosing LAmB by adjBW may be reasonable in patients who are not critically ill and who have lower risk infections. In critically ill patients or those with fungal pathogens or sites of infection associated with higher mortality risk, dosing by TBW can be considered.Cefiderocol (CFDC), a novel siderophore cephalosporin, demonstrates strong activity against multidrug-resistant (MDR) Acinetobacter baumannii. Limited studies have evaluated CFDC alone and in combination with other Gram-negative antibiotics against MDR A. baumannii isolates. Susceptibility testing revealed lower CFDC minimum inhibitory concentration (MIC) values than the comparator Gram-negative agents (87% of MICs ≤ 4mg/L). Six isolates, with elevated CFDC MICs (16-32 mg/L), were selected for further experiments. Time-kill analyses presented with synergistic activity and beta-lactamase inhibitors increased CFDC susceptibility in each of the isolates.Background Methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia has a high case-fatality rate, but currently recommended antimicrobial therapies have many shortcomings. The efficacy and safety of lincosamide therapy for MRSA bacteraemia is incompletely defined. Materials and methods A retrospective audit of the management of all adults with MRSA bacteraemia at an Australian tertiary-referral hospital between 1 January 2007 and 31 December 2020. Results 176 patients were included. The case-fatality rate declined from 14/57 (25%) in the first half of the study to 12/119 (10%) in the second half (p=0.01). Of the 172 patients receiving antibiotics, 62 (36%) received a lincosamide-predominant regimen (lincosamide monotherapy for >50% of the intravenous course). The patients receiving lincosamide-predominant intravenous therapy had lower in-hospital mortality (odds ratio (OR) 0.07 (95% confidence interval (CI) 0.01-0.53), p=0.01) and a lower incidence of renal complications (OR (95% CI) 0.34 (0.15-0.75), p=0.008) than patients receiving an alternative regimen. In multivariate analysis that also considered age, disease severity, comorbidity, infectious diseases consultation, source control and the year of admission, patients receiving a lincosamide-predominant regimen were still less likely to die in hospital than those receiving an alternative regimen (OR (95% CI) 0.05 (0.00-0.65), p=0.02). Conclusions Lincosamides appear to have utility - at least as stepdown therapy - in the treatment of MRSA bacteremia, particularly in young, clinically stable patients with few comorbidities in whom endocarditis has been excluded. Prospective studies will help define their optimal role.Among the most common metallo-β-lactamases (MBL), the most clinically significant are the New Delhi Metallo-β-lactamases (NDM). NDM enzymes hydrolyze almost all β-lactams except aztreonam and are not inhibited by novel β-lactamase inhibitors such as avibactam (AVI), relebactam, and vaborbactam (1).….Azole resistance of Aspergillus fumigatus is a global problem. The major resistant mechanism is a cytochrome P450 14-α sterol demethylase Cyp51A alteration such as mutation(s) in the gene and the acquisition of a tandem repeat in the promoter. Although other azole tolerances and resistant mechanisms such as hmg1 (a 3-hydroxy-3-methylglutaryl-coenzyme-A reductase gene) mutation are known, few reports have described studies elucidating non-Cyp51A resistance mechanisms. This study explored genes contributing to azole tolerance in A. fumigatus by in vitro mutant selection with tebuconazole, an azole fungicide. After three-round selection, we obtained four isolates with low susceptibility to tebuconazole. These isolates also showed low susceptibility to itraconazole and voriconazole. Comparison of the genome sequences of the obtained isolates and the parental strain revealed a non-synonymous mutation in MfsD for a major facilitator superfamily protein (Afu1g11820, R337L mutation) in all isolates. Furthermore, non-synonymous mutations in AgcA for a mitochondrial inner membrane aspartate/glutamate transporter (Afu7g05220, E535Stop mutation), UbcD for a ubiquitin-conjugating enzyme E2 (Afu3g06030, T98K mutation), AbcJ for an ABC transporter (Afu3g12220, G297E mutation), and RttA for a putative protein responsible for tebuconazole tolerance (Afu7g04740, A83T mutation), were found in at least one isolate.