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Clostridium difficile is an anaerobic, Gram-positive, spore-forming opportunistic pathogen and is the most common cause of hospital-acquired infectious diarrhea. Although iron acquisition in the host is a key to survival of bacterial pathogens, high levels of intracellular iron can increase oxidative damage. Therefore, expression of iron acquisition mechanisms is tightly controlled by transcriptional regulators. We identified aC. difficile homologue of the master bacterial iron regulator Fur. Using targetron mutagenesis, we generated afur insertion mutant ofC. difficile . To identify the genes regulated by Fur inC. difficile , we used microarray analysis to compare transcriptional differences between thefur mutant and the wild type when grown in high-iron medium. Thefur mutant had increased expression of greater than 70 transcriptional units. Using quantitative reverse transcriptase PCR (qRT-PCR), we analyzed several of the Fur-regulated genes identified by the microarray and verified that they are both iron and Fur regulated inC. difficile . Among those Fur- and iron-repressed genes wereC. difficile genes encoding 7 putative cation transport systems of different classes. We found that Fur was able to bind the DNA upstream of three Fur-repressed genes in electrophoretic mobility shift assays. We also demonstrate that expression of Fur-regulated putative iron acquisition systems was increased duringC. difficile infection using the hamster model. Our data suggest thatC. difficile expresses multiple iron transport mechanisms in response iron depletionin vitro andin vivo .IMPORTANCE Clostridium difficile is the most common cause of hospital-acquired infectious diarrhea and has been recently classified as an “urgent” antibiotic resistance threat by the CDC. To survive and cause disease, most bacterial pathogens must acquire the essential enzymatic cofactor iron. While import of adequate iron is essential for most bacterial growth, excess intracellular iron can lead to extensive oxidative damage. Thus, bacteria must regulate iron import to maintain iron homeostasis. We demonstrate here thatC. difficile regulates expression of several putative iron acquisition systems using the transcriptional regulator Fur. These import mechanisms are induced under iron-limiting conditionsin vitro and duringC. difficile infection of the host. This suggests that during aC. difficile infection, iron availability is limitedin vivo .

Ferric Uptake Regulator Fur Control of Putative Iron Acquisition Systems in Clostridium difficile