Synthesis and biochemical characterization of naphthoquinone derivatives targeting bacterial histidine kinases.

Waldiomycin is an inhibitor of histidine kinases (HKs). Although most HK inhibitors target the ATP-binding region, waldiomycin binds to the intracellular dimerization domain (DHp domain) with its naphthoquinone moiety presumed to interact with the conserved H-box region. To further develop inhibitors targeting the H-box, various 2-aminonaphthoquinones with cyclic, aliphatic, or aromatic amino groups and naphtho [2,3-d] isoxazole-4,9-diones were synthesized.

Diffusible signal factors (DSFs) bind and repress VirF, the leading virulence activator of Shigella flexneri.

Shigella, the aetiological agent of human bacillary dysentery, controls the expression of its virulence determinants through an environmentally stimulated cascade of transcriptional activators. VirF is the leading activator and is essential for proper virulence expression. In this work, we report on in vitro and in vivo experiments showing that two autoinducers of the DSF family, XcDSF and BDSF interact with the jelly roll module of VirF causing its inhibition and affecting the expression of the entire virulence system of Shigella, including its ability to invade epithelial cells.

Role of the MDR Efflux Pump AcrAB in Epithelial Cell Invasion by .

The tripartite complex AcrAB-TolC is the major RND pump in and other Enterobacteriaceae, including , the etiological agent of bacillary dysentery. In addition to conferring resistance to many classes of antibiotics, AcrAB plays a role in the pathogenesis and virulence of several bacterial pathogens. Here, we report data demonstrating that AcrAB specifically contributes to invasion of epithelial cells.

Fatty Acids Abolish Virulence by Inhibiting Its Master Regulator, VirF.

The pathogenicity of , the intracellular pathogen responsible for human bacillary dysentery, depends on a coordinated and tightly regulated expression of its virulence determinants. This is the result of a cascade organization of its positive regulators, with VirF, a transcriptional activator belonging to the AraC-XylS family, in a pivotal position. VirF itself is submitted to several well-known regulations at the transcriptional level.

AcrAB efflux pump impacts on the survival of adherent-invasive Escherichia coli strain LF82 inside macrophages.

The tripartite complex AcrAB-TolC is the major RND pump in Escherichia coli and other Enterobacteriaceae. It consists of the AcrB transporter, which is embedded in the inner membrane, the AcrA adapter located in the periplasm, and the channel protein TolC responsible for the transport of substrates towards the extracellular environment. Besides conferring resistance to many classes of antibiotics, AcrAB plays a role in the pathogenesis and virulence of several bacterial pathogens.

Roles of Two-Component Signal Transduction Systems in Shigella Virulence.

Two-component signal transduction systems (TCSs) are widespread types of protein machinery, typically consisting of a histidine kinase membrane sensor and a cytoplasmic transcriptional regulator that can sense and respond to environmental signals. TCSs are responsible for modulating genes involved in a multitude of bacterial functions, including cell division, motility, differentiation, biofilm formation, antibiotic resistance, and virulence. Pathogenic bacteria exploit the capabilities of TCSs to reprogram gene expression according to the different niches they encounter during host infection.

The VirF21:VirF30 protein ratio is affected by temperature and impacts Shigella flexneri host cell invasion.

Shigella spp, the etiological agents of bacillary dysentery in humans, have evolved an intricate regulatory strategy to ensure fine-tuned expression of virulence genes in response to environmental stimuli. A key component in this regulation is VirF, an AraC-like transcription factor, which at the host temperature (37°C) triggers, directly or indirectly, the expression of > 30 virulence genes important for invasion of the intestinal epithelium. Previous work identified two different forms of VirF with distinct functions: VirF30 activates virulence gene expression, while VirF21 appears to negatively regulate virF itself.

Host - Bacterial Pathogen Communication: The Wily Role of the Multidrug Efflux Pumps of the MFS Family.

Bacterial pathogens are able to survive within diverse habitats. The dynamic adaptation to the surroundings depends on their ability to sense environmental variations and to respond in an appropriate manner. This involves, among others, the activation of various cell-to-cell communication strategies.

Modulation of OMV Production by the Lysis Module of the DLP12 Defective Prophage of .

Outer membrane vesicles (OMVs) are nanostructures mostly produced by blebbing of the outer membrane in Gram negative bacteria. They contain biologically active proteins and perform a variety of processes. OMV production is also a typical response to events inducing stress in the bacterial envelope.

An application to support COVID-19 occupational health and patient tracking at a Veterans Affairs medical center.

Objective: Reducing risk of coronavirus disease 2019 (COVID-19) infection among healthcare personnel requires a robust occupational health response involving multiple disciplines. We describe a flexible informatics solution to enable such coordination, and we make it available as open-source software.

Materials And Methods: We developed a stand-alone application that integrates data from several sources, including electronic health record data and data captured outside the electronic health record.

Expression Profile of Multidrug Resistance Efflux Pumps During Intracellular Life of Adherent-Invasive Strain LF82.

Efflux pumps (EPs) are present in all living cells and represent a large and important group of transmembrane proteins involved in transport processes. In bacteria, multidrug resistance efflux pumps (MDR EPs) confer resistance to antibiotics at different levels and are deeply implicated in the fast and dramatic emergence of antibiotic resistance. Recently, several reports have outlined the great versatility of MDR EPs in exporting a large variety of compounds other than antibiotics, thus promoting bacterial adaptation to a wide range of habitats.

The Varied Role of Efflux Pumps of the MFS Family in the Interplay of Bacteria with Animal and Plant Cells.

Efflux pumps represent an important and large group of transporter proteins found in all organisms. The importance of efflux pumps resides in their ability to extrude a wide range of antibiotics, resulting in the emergence of multidrug resistance in many bacteria. Besides antibiotics, multidrug efflux pumps can also extrude a large variety of compounds: Bacterial metabolites, plant-produced compounds, quorum-sensing molecules, and virulence factors.

Author Correction: The MFS efflux pump EmrKY contributes to the survival of Shigella within macrophages.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

The MFS efflux pump EmrKY contributes to the survival of Shigella within macrophages.

Efflux pumps are membrane protein complexes conserved in all living organisms. Beyond being involved in antibiotic extrusion in several bacteria, efflux pumps are emerging as relevant players in pathogen-host interactions. We have investigated on the possible role of the efflux pump network in Shigella flexneri, the etiological agent of bacillary dysentery.

The Intriguing Evolutionary Journey of Enteroinvasive (EIEC) toward Pathogenicity.

Among the intestinal pathogenic , enteroinvasive (EIEC) are a group of intracellular pathogens able to enter epithelial cells of colon, multiplicate within them, and move between adjacent cells with a mechanism similar to , the ethiological agent of bacillary dysentery. Despite EIEC belong to the same pathotype of , they neither have the full set of traits that define nor have undergone the extensive gene decay observed in . Molecular analysis confirms that EIEC are widely distributed among phylogenetic groups and correspond to bioserotypes found in many serogroups.

Role of the SRRz/Rz lambdoid lysis cassette in the pathoadaptive evolution of Shigella.

Shigella, the etiological agent of bacillary dysentery (shigellosis), is a highly adapted human pathogen. It evolved from an innocuous ancestor resembling the Escherichia coli strain by gain and loss of genes and functions. While the gain process concerns the acquisition of the genetic determinants of virulence, the loss is related to the adaptation of the genome to the new pathogenic status and occurs by pathoadaptive mutation of antivirulence genes.

One Gene and Two Proteins: a Leaderless mRNA Supports the Translation of a Shorter Form of the Shigella VirF Regulator.

Unlabelled: VirF, an AraC-like activator, is required to trigger a regulatory cascade that initiates the invasive program of Shigella spp., the etiological agents of bacillary dysentery in humans. VirF expression is activated upon entry into the host and depends on many environmental signals.

The Multifaceted Activity of the VirF Regulatory Protein in the Lifestyle.

is a highly adapted human pathogen, mainly found in the developing world and causing a severe enteric syndrome. The highly sophisticated infectious strategy of banks on the capacity to invade the intestinal epithelial barrier and cause its inflammatory destruction. The cellular pathogenesis and clinical presentation of shigellosis are the sum of the complex action of a large number of bacterial virulence factors mainly located on a large virulence plasmid (pINV).

Global phylogeography and evolutionary history of Shigella dysenteriae type 1.

Together with plague, smallpox and typhus, epidemics of dysentery have been a major scourge of human populations for centuries(1). A previous genomic study concluded that Shigella dysenteriae type 1 (Sd1), the epidemic dysentery bacillus, emerged and spread worldwide after the First World War, with no clear pattern of transmission(2). This is not consistent with the massive cyclic dysentery epidemics reported in Europe during the eighteenth and nineteenth centuries(1,3,4) and the first isolation of Sd1 in Japan in 1897(5).

Multifactor Regulation of the MdtJI Polyamine Transporter in Shigella.

The polyamine profile of Shigella, the etiological agent of bacillary dysentery in humans, differs markedly from that of E. coli, its innocuous commensal ancestor. Pathoadaptive mutations such as the loss of cadaverine and the increase of spermidine favour the full expression of the virulent phenotype of Shigella.

Molecular and functional profiling of the polyamine content in enteroinvasive E. coli : looking into the gap between commensal E. coli and harmful Shigella.

Polyamines are small molecules associated with a wide variety of physiological functions. Bacterial pathogens have developed subtle strategies to exploit polyamines or manipulate polyamine-related processes to optimize fitness within the host. During the transition from its innocuous E.

Molecular evolution of the nicotinic acid requirement within the Shigella/EIEC pathotype.

Nicotinamide adenine dinucleotide (NAD) is a crucial cofactor in several anabolic and catabolic reactions. NAD derives from quinolinic acid (QUIN) which in Escherichia coli is obtained through a pyridine salvage pathway or a de novo synthesis pathway. In the latter case, two enzymes, L-aspartate oxidase (NadB) and quinolinate synthase (NadA), are required for the synthesis of QUIN.

Polyamines: emerging players in bacteria-host interactions.

Polyamines are small polycationic molecules found in almost all cells and associated with a wide variety of physiological processes. In recent years it has become increasingly clear that, in addition to core physiological functions, polyamines play a crucial role in bacterial pathogenesis. Considerable evidence has built up that bacteria have evolved mechanisms to turn these molecules to their own advantage and a novel standpoint to look at host-bacterium interactions emerges from the interplay among polyamines, host cells and infecting bacteria.