JA, MZ, MCCV and MJB conceived the study, participated in the study design E2 conjugating inhibitor process, and helped write the manuscript. All authors read and approved the final manuscript.”
“Background Yersinia pestis, a Gram-negative bacterium, is the causative agent of the bubonic and pneumonic plague. The pathogenic lifestyle of this microbe involves two distinct life stages, one in the flea vector, the other in mammalian hosts, primarily rodents [1]. Genome
sequencing and analyses have been completed for four major Y. pestis biovars, including the chromosome [2] and three virulence/transmission-associated plasmids [3, 4] of the KIM strain, which belongs to the biovar mediaevalis. In addition to plasmid-encoded virulence selleck chemical factors, the genetically unstable chromosomal 102-kb pgm locus is also important for full virulence of Y. pestis in mammals and for its transmission via blocked fleas [5, 6]. This
locus encodes the yersiniabactin-dependent iron transport (Ybt) system and the hemin storage (Hms)-dependent biofilm system. Biofilm formation allows colonization of the flea proventriculus causing blockage which in turn induces active feeding behavior [7, 8]. Efficient iron acquisition systems are critical to the ability of Yersinia pestis to infect, spread and grow in mammalian hosts, because iron is sequestered and is considered part of the innate host immune defence against invading pathogens [9]. The Ybt system includes a series of enzymes responsible for the siderophore’s CAL-101 in vitro biosynthesis. Following secretion and iron chelation, the iron/yersiniabactin complex is bound by the outer membrane (OM) receptor Psn and transferred into the periplasm via TonB-dependent energy transmission. Binding of the complex to the periplasmic surface of the inner membrane-localized ATP-binding cassette (ABC) transporter YbtP/YbtQ, which contains two permease and two ATP-binding domains, initiates iron import Cediranib (AZD2171) into the cytoplasm. A functional Ybt transporter is required for bacterial infection by subcutaneous
routes and important for iron acquisition in early stages of the bubonic plague in mice [10–12]. The manganese- and iron-specific ABC transporter Yfe is also important for full Y. pestis virulence according to data from a bubonic plague mouse model [13]. Other ABC transporters for iron (Yfu and Yiu) and hemin (Hmu) were functionally characterized, but were not found to be required for virulence in the mouse model [14–16]. The transporters Yfe and Feo serve somewhat redundant roles in ferrous iron uptake under microaerophilic growth conditions [17]. Genomic analysis suggests the existence of other transporters and OM receptors for iron/siderophores but have not been functionally characterized to date [2, 18]. The ferric uptake regulator Fur is a dominant transcription factor controlling iron assimilation in many bacterial species [19].