Moreover, we were intrigued to find that BsaN suppresses a second PKS/NRPS cluster (BPSS0130, BPSS0303-BPSS0311, BPSS0328-BPSS0339) (Table 2), where almost identical homologs were identified in B. mallei and B. thailandensis by Biggins et al. and shown to produce an iron-chelating siderophore called www.selleckchem.com/products/AZD8931.html malleilactone [45]. Disruption of the MAL

cluster in B. thailandensis reduced lethality following infection of C. elegans, and purified malleilactone was toxic to mammalian cells at micromolar concentrations. How the function of MAL fits within an overall regulatory framework that promotes virulence is not clear, although it is conceivable that BsaN-mediated suppression of MAL reduces the production of toxic products during infection, thereby promoting long term survival

within eukaryotic hosts. Alternatively, malleilactone itself may regulate virulence factor production similar to that reported for the P. aeruginosa siderophore pyoverdine [46]. Figure 7 Diagram of BsaN regulon. The BsaN regulon is shown selleck products as part of a regulatory network, which is superseded by BprP activating transcriptions of T3SS3 apparatus genes (blue) including bsaN. The bicA gene is likely initially transcribed via read through of apparatus genes. BsaN-BicA function as a complex to activate T3SS3 Barasertib translocon (purple), effector (yellow), accessory (grey) and regulatory (red) genes. Transcriptional activation is indicated by green arrows. BsaN-BicA also activate virAG, which in turn activates the bimA motility genes and the T6SS1 locus. BprC activates the T6SS1 tssAB apparatus genes. BsaN-BicA also activate a non-ribosomal polyketide synthesis locus and several metabolic genes. BsaN-repressed genes as indicated by red, blunted lines include T3SS3 apparatus genes and flagellar motility genes. Only genes which have been validated by qRT-PCR are shown. Until recently, BopA and BopE were the only two known T3SS

effector proteins in B. pseudomallei. The dearth of effectors is surprising when compared to other intracellular pathogens such as Shigella and Salmonella that are known to possess numerous effectors. We have independently identified BopC (BPSS1516) as a new T3SS3 effector based on its regulatory control by BsaN/BicA. bopC is transcribed in an operon encoding its chaperone (BPSS1517) and a transposase (BPSS1518) that are also activated by BsaN/BicA. Incidentally, Morin Hydrate we had previously predicted by a genome-wide screen that BPSS1516 would encode a T3SS effector based on genomic colocalization with T3SS chaperones [47]. The BsaN regulatory motif we found in the promoters of the effectors was also recently reported to be associated with T3SS3 in a condition-dependent transcriptome study [48]. Of the T3SS3-linked effector proteins; BopA, BopC and BopE, our results suggest that BopA is the most critical for promoting cellular infection, consistent with prior studies linking BopA to intracellular survival of B.