bis(3--5-)-cyclic-diguanylic-acid and Cross-Infection

In the past decade, Clostridium difficile has emerged as an important gut pathogen. This anaerobic, Gram-positive bacterium is the main cause of infectious nosocomial diarrhea. Whereas much is known about the mechanism through which the C. difficile toxins cause diarrhea, relatively little is known about the dynamics of adhesion and motility, which is mediated by cell surface proteins. This review will discuss the recent advances in our understanding of the sortase-mediated covalent attachment of cell surface (adhesion) proteins to the peptidoglycan layer of C. difficile and their release through the action of a highly specific secreted metalloprotease (Pro-Pro endopeptidase 1, PPEP-1). Specific emphasis will be on a model in which PPEP-1 and its substrates control the switch from a sessile to motile phenotype in C. difficile, and how this is regulated by the cyclic dinucleotide c-di-GMP (3'-5' cyclic dimeric guanosine monophosphate).

Topics: Bacterial Proteins; Biofilms; Cell Adhesion; Clostridioides difficile; Cross Infection; Cyclic GMP; Dipeptides; Endopeptidases; Gene Expression Regulation, Bacterial; Humans; Membrane Proteins; Metalloproteases; Peptidoglycan

The Gram-negative opportunistic pathogen Klebsiella pneumoniae is responsible for causing a spectrum of nosocomial and community-acquired infections. Globally, K. pneumoniae is a frequently encountered hospital-acquired opportunistic pathogen that typically infects patients with indwelling medical devices. Biofilm formation on these devices is important in the pathogenesis of these bacteria, and in K. pneumoniae, type 3 fimbriae have been identified as appendages mediating the formation of biofilms on biotic and abiotic surfaces. The factors influencing the regulation of type 3 fimbrial gene expression are largely unknown but recent investigations have indicated that gene expression is regulated, at least in part, by the intracellular levels of cyclic di-GMP. In this review, we have highlighted the recent studies that have worked to elucidate the mechanism by which type 3 fimbrial expression is controlled and the studies that have established the importance of type 3 fimbriae for biofilm formation and nosocomial infection by K. pneumoniae.

Topics: Biofilms; Catheter-Related Infections; Community-Acquired Infections; Cross Infection; Cyclic GMP; Fimbriae, Bacterial; Gene Expression Regulation, Bacterial; Humans; Klebsiella Infections; Klebsiella pneumoniae; Virulence Factors

c-di-GMP is a cellular second messenger that regulates diverse bacterial processes, including swimming, biofilm formation and virulence. However, in Stenotrophomonas maltophilia, a nosocomial pathogen that frequently infects immunodeficient or immunoincompetent patients, the regulatory function of c-di-GMP remains unclear. Here we show that BsmR is a negative regulator of biofilm development that degrades c-di-GMP through its EAL domain. Increasing BsmR expression resulted in significant increase in bacterial swimming and decrease in cell aggregation. BsmR regulates the expression of at least 349 genes. Among them, 34 involved in flagellar assembly and a flagellar-assembly-related transcription factor (fsnR) are positively regulated. Although BsmR is a response regulator of the two-component signaling system, its role in biofilm formation depends on the expression level of its respective gene (bsmR), not on the protein's phosphorylation level. A transcription factor, BsmT, whose coding gene is located in the same tetra-cistronic operon as bsmR, was shown to directly bind to the promoter region of the operon and, through a positive regulatory loop, modulate bsmR transcription. Thus, our results revealed that the c-di-GMP signaling pathway controls biofilm formation and swimming in S. maltophilia, suggesting c-di-GMP signaling as a target in the development of novel antibacterial agents to resist this pathogen.

Topics: Bacterial Proteins; Binding Sites; Biofilms; Cross Infection; Cyclic GMP; Gene Expression Profiling; Gene Expression Regulation, Bacterial; High-Throughput Nucleotide Sequencing; Operon; Phosphorylation; Promoter Regions, Genetic; Protein Binding; Sequence Analysis, RNA; Signal Transduction; Stenotrophomonas maltophilia