Many Gram-negative bacteria interact
with extracellular metal ions
by expressing one or more siderophore types. Among these, the virulence-associated
siderophore yersiniabactin (Ybt) is an avid copper chelator, forming
stable cupric (Cu(II)-Ybt) complexes that are detectable in infected
patients. Here we show that Ybt-expressing E. coli are protected from intracellular killing within copper-replete phagocytic
cells. This survival advantage is highly dependent upon the phagocyte
respiratory burst, during which superoxide is generated by the NADPH
oxidase complex. Chemical fractionation links this phenotype to a
previously unappreciated superoxide dismutase (SOD)-like activity
of Cu(II)-Ybt. Unlike previously described synthetic copper-salicylate
(Cu(II)-SA) SOD mimics, the salicylate-based natural product Cu(II)-Ybt
retains catalytic activity at physiologically plausible protein concentrations.
These results reveal a new virulence-associated adaptation based upon
spontaneous assembly of a non-protein catalyst.
Bacterial pathogens are becoming increasingly resistant to antibiotics. As an alternative therapeutic strategy, phage therapy reagents containing purified viral lysins have been developed against Grampositive organisms but not against Gram-negative organisms due to the inability of these types of drugs to cross the bacterial outer membrane. We solved the crystal structures of a Yersinia pestis outer membrane transporter called FyuA and a bacterial toxin called pesticin that targets this transporter. FyuA is a β-barrel membrane protein belonging to the family of TonB dependent transporters, whereas pesticin is a soluble protein with two domains, one that binds to FyuA and another that is structurally similar to phage T4 lysozyme. The structure of pesticin allowed us to design a phage therapy reagent comprised of the FyuA binding domain of pesticin fused to the N-terminus of T4 lysozyme. This hybrid toxin kills specific Yersinia and pathogenic E. coli strains and, importantly, can evade the pesticin immunity protein (Pim) giving it a distinct advantage over pesticin. Furthermore, because FyuA is required for virulence and is more common in pathogenic bacteria, the hybrid toxin also has the advantage of targeting primarily disease-causing bacteria rather than indiscriminately eliminating natural gut flora.colicin | muramidase | TonB-dependent transport | plague
Recent findings suggest that both host and pathogen manipulate copper content in infected host niches during infections. In this review, we summarize recent developments that implicate copper resistance as an important determinant of bacterial fitness at the host-pathogen interface. An essential mammalian nutrient, copper cycles between copper (I) (Cu+) in its reduced form and copper (II) (Cu2+) in its oxidized form under physiologic conditions. Cu+ is significantly more bactericidal than Cu2+ due to its ability to freely penetrate bacterial membranes and inactivate intracellular iron-sulfur clusters. Copper ions can also catalyze reactive oxygen species (ROS) generation, which may further contribute to their toxicity. Transporters, chaperones, redox proteins, receptors and transcription factors and even siderophores affect copper accumulation and distribution in both pathogenic microbes and their human hosts. This review will briefly cover evidence for copper as a mammalian antibacterial effector, the possible reasons for this toxicity, and pathogenic resistance mechanisms directed against it.
Metabolomic profiling offers direct insights into the chemical environment and metabolic pathway activities at sites of human disease. During infection, this environment may receive important contributions from both host and pathogen. Here we apply untargeted metabolomics approach to identify compounds associated with an E. coli urinary tract infection population. Correlative and structural data from minimally processed samples were obtained using an optimized LC-MS platform capable of resolving ∼2300 molecular features. Principal components analysis readily distinguished patient groups and multiple supervised chemometric analyses resolved robust metabolomic shifts between groups. These analyses revealed nine compounds whose provisional structures suggest candidate infection-associated endocrine, catabolic, and lipid pathways. Several of these metabolite signatures may derive from microbial processing of host metabolites. Overall, this study highlights the ability of metabolomic approaches to directly identify compounds encountered by, and produced from, bacterial pathogens within human hosts.
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