Svenningsenskovsgaard3547

Hypervirulent Klebsiella pneumoniae strains are the major causes of liver abscesses throughout East Asia, and these strains are usually antibiotic susceptible. Recently, multidrug resistant and hypervirulent (MDR-HV) K. pneumoniae strain emerged, arisen by hypervirulent strains acquiring antimicrobial resistance determinants or the transfer of a virulence plasmid into a classic MDR strain. In this study, we characterized the clinical and microbiological properties of K. pneumoniae liver abscess (KPLA) caused by MDR-HV strains in Taiwan. Patients with community-onset KPLA were retrospectively identified at Taipei Veterans General Hospital during January 2013 and May 2018. Antimicrobial resistance mechanisms, capsular types, and sequence types were determined. MDR-HV strains and their parental antimicrobial-susceptible strains further underwent whole genome sequencing (WGS) and in vivo mice lethality test. Thirteen MDR-HV strains were identified from a total of 218 KPLA episodes. MDR-HV strains resulted in similar outcomes to antimicrobial-susceptible strains. All MDR-HV strains were traditional hypervirulent clones carrying virulence capsular types. The major resistance mechanisms were the overexpression of efflux pumps and/or the acquisition of ESBL or AmpC β-lactamase genes. WGS showed two hypervirulent strains evolved to MDR phenotype after having a mutation in ramR and acquiring a SHV-12-bearing plasmid, respectively. Both the MDR-HV strains retained high virulence in comparison to their parental strains. The spread of MDR-HV K. pneumoniae strains in the community raises significant public concerns, and measures should be taken to prevent the further acquisition of carbapenemase and other resistance genes among these strains in order to avoid the occurrence of untreatable KPLA. Copyright © 2020 American Society for Microbiology.Plazomicin was tested against 697 recently acquired carbapenem resistant Klebsiella pneumoniae isolates from the Great Lakes Region of the United States. Plazomicin MIC50 and MIC90 values were 0.25 and 1 mg/L, respectively; 680 isolates were susceptible (97.6%, MIC ≤ 2 mg/L), 9 intermediate (1.3%, MIC 4mg/L), and 8 resistant (1.1%, MIC > 32 mg/L). Resistance was associated with rmtF-, rmtB- or armA-encoded 16S ribosomal RNA methyltransferases, in all but one isolate. Copyright © 2020 American Society for Microbiology.Fluoroquinolones are reported to possess immunomodulatory activity; hence a novel benzoquinolizine fluoroquinolone levonadifloxacin was evaluated in lipopolysaccharide (LPS) stimulated human whole blood (HWB) and mice acute lung injury (ALI) models. Levonadifloxacin significantly mitigated the inflammatory responses in HWB assay through inhibition of pro-inflammatory cytokines and in ALI model by lowering lung total white blood cell count, myeloperoxidase and cytokines levels. The immunomodulatory effect of levonadifloxacin along with promising antibacterial activity is expected to provide clinical benefits in the treatment of infections. Copyright © 2020 American Society for Microbiology.Advances in synthetic biology have enabled production of a variety of compounds using bacteria as a vehicle for complex compound biosynthesis. Violacein, a naturally occurring indole pigment with antibiotic properties, can be biosynthetically engineered in Escherichia coli expressing its non-native synthesis pathway. check details To explore whether this synthetic biosynthesis platform could be used for drug discovery, here we have screened bacterially-derived violacein against the main causative agent of human malaria, Plasmodium falciparum We show the antiparasitic activity of bacterially-derived violacein against the P. falciparum 3D7 laboratory reference strain as well as drug-sensitive and resistant patient isolates, confirming the potential utility of this drug as an antimalarial. We then screen a biosynthetic series of violacein derivatives against P. falciparum growth. The demonstrated varied activity of each derivative against asexual parasite growth points to potential for further development of violacein as an antimalarial. Towards defining its mode of action, we show that biosynthetic violacein affects the parasite actin cytoskeleton, resulting in an accumulation of actin signal that is independent of actin polymerization. This activity points to a target that modulates actin behaviour in the cell either in terms of its regulation or its folding. More broadly, our data show that bacterial synthetic biosynthesis could become a suitable platform for antimalarial drug discovery with potential applications in future high-throughput drug screening with otherwise chemically-intractable natural products. Copyright © 2020 Wilkinson et al.Ceftobiprole is an advanced generation broad-spectrum cephalosporin antibiotic with potent and rapid bactericidal activity against Gram-positive pathogens including methicillin-resistant S. aureus (MRSA) as well as susceptible Gram-negative pathogens including Pseudomonas spp, pathogens. In the case of Pseudomonas aeruginosa ceftobiprole acts by inhibiting P. aeruginosa PBP3. Structural studies were pursued to elucidate the molecular details of this PBP inhibition. The crystal structure of the His-tagged PBP3Ceftobiprole complex revealed a covalent bond between the ligand and the catalytic residue S294. Ceftobiprole binding leads to large active site changes near binding sites for the pyrrolidinone and pyrrolidine rings. The S528-L536 region adopts a conformation previously not observed in PBP3 including a partial unwinding of the α11 helix. These molecular insights can lead to a deeper understanding of β-lactamPBP interactions that result in major changes in protein structure as well as how to fine-tune current and develop novel inhibitors of this PBP. Copyright © 2020 American Society for Microbiology.In the past few decades, Enterovirus A71 (EVA71) has caused devastating outbreaks in the Asia-Pacific region resulting in serious sequelae in infected young children. No preventive and therapeutic interventions are currently available for curing EVA71 infection, highlighting a great unmet medical need for this disease. Here, we showed that one novel single domain antibody (sdAb, F1) isolated from an immunized llama could alleviate EVA71 infection, both in vitro and in vivo We also confirmed that the sdAb clone F1 recognizes EVA71 through a novel conformational epitope comprising the highly conserved region of VP3 capsid protein by using competitive-binding and overlapping-peptide ELISA assays. Because of the virion's icosahedral structure, we reasoned that adjacent epitopes must be clustered within molecular ranges that may be simultaneously bound by an engineered antibody with multiple valency. Therefore, two single domain binding modules (F1) were fused to generate an sdAb-in-tandem design so that the capture of viral antigens can be further increased by valency effects.