Dysbiosis-associated gut bacterium varies at the strain level in its ability to utilize key mucin component sialic acid.

Unlabelled: is a prevalent human gut commensal bacterium with known roles in intestinal mucus degradation, including by catabolism of the terminal mucin sugar sialic acid. While is not considered a pathogen, overabundance of this species is correlated with inflammatory bowel disease (IBD), and its sialic acid metabolism may play a role in the dysbiotic state. Interestingly, liberation of mucin-bound sialic acid by yields the distinct product of 2,7-anhydro-N-acetylneuraminic acid (2,7-anhydro-Neu5Ac), in contrast to other known mucin-degrading bacteria, which generate Neu5Ac.

Discovery of potent dihydro-oxazinoquinolinone inhibitors of GuaB for the treatment of tuberculosis.

Tuberculosis is the leading cause of death from an infectious disease, and is caused by Mycobacterium tuberculosis (M.tb). More than 1 billion people worldwide are thought to harbor an M.

The aryl hydrocarbon receptor and FOS mediate cytotoxicity induced by Acinetobacter baumannii.

Acinetobacter baumannii is a pathogenic and multidrug-resistant Gram-negative bacterium that causes severe nosocomial infections. To better understand the mechanism of pathogenesis, we compare the proteomes of uninfected and infected human cells, revealing that transcription factor FOS is the host protein most strongly induced by A. baumannii infection.

Differential effects of inosine monophosphate dehydrogenase (IMPDH/GuaB) inhibition in and .

Inosine 5'-monophosphate dehydrogenase (IMPDH), known as GuaB in bacteria, catalyzes the rate-limiting step in guanine biosynthesis and is conserved from humans to bacteria. We developed a series of potent inhibitors that selectively target GuaB over its human homolog. Here, we show that these GuaB inhibitors are bactericidal, generate phenotypic signatures that are distinct from other antibiotics, and elicit different time-kill kinetics and regulatory responses in two important Gram-negative pathogens: and .

Discovery of GuaB inhibitors with efficacy against infection.

Unlabelled: Guanine nucleotides are required for growth and viability of cells due to their structural role in DNA and RNA, and their regulatory roles in translation, signal transduction, and cell division. The natural antibiotic mycophenolic acid (MPA) targets the rate-limiting step in guanine nucleotide biosynthesis executed by inosine-5´-monophosphate dehydrogenase (IMPDH). MPA is used clinically as an immunosuppressant, but whether inhibition of bacterial IMPDH (GuaB) is a valid antibacterial strategy is controversial.

Alternative therapeutic strategies to treat antibiotic-resistant pathogens.

Resistance threatens to render antibiotics - which are essential for modern medicine - ineffective, thus posing a threat to human health. The discovery of novel classes of antibiotics able to overcome resistance has been stalled for decades, with the developmental pipeline relying almost entirely on variations of existing chemical scaffolds. Unfortunately, this approach has been unable to keep pace with resistance evolution, necessitating new therapeutic strategies.

Bacterial biofilms in the human body: prevalence and impacts on health and disease.

Bacterial biofilms can be found in most environments on our planet, and the human body is no exception. Consisting of microbial cells encased in a matrix of extracellular polymers, biofilms enable bacteria to sequester themselves in favorable niches, while also increasing their ability to resist numerous stresses and survive under hostile circumstances. In recent decades, biofilms have increasingly been recognized as a major contributor to the pathogenesis of chronic infections.

Returning to Nature for the Next Generation of Antimicrobial Therapeutics.

Antibiotics found in and inspired by nature are life-saving cures for bacterial infections and have enabled modern medicine. However, the rise in resistance necessitates the discovery and development of novel antibiotics and alternative treatment strategies to prevent the return to a pre-antibiotic era. Once again, nature can serve as a source for new therapies in the form of natural product antibiotics and microbiota-based therapies.

IL-22 alters gut microbiota composition and function to increase aryl hydrocarbon receptor activity in mice and humans.

Background: IL-22 is induced by aryl hydrocarbon receptor (AhR) signaling and plays a critical role in gastrointestinal barrier function through effects on antimicrobial protein production, mucus secretion, and epithelial cell differentiation and proliferation, giving it the potential to modulate the microbiome through these direct and indirect effects. Furthermore, the microbiome can in turn influence IL-22 production through the synthesis of L-tryptophan (L-Trp)-derived AhR ligands, creating the prospect of a host-microbiome feedback loop. We evaluated the impact IL-22 may have on the gut microbiome and its ability to activate host AhR signaling by observing changes in gut microbiome composition, function, and AhR ligand production following exogenous IL-22 treatment in both mice and humans.

The role of bacterial membrane vesicles in antibiotic resistance.

Bacterial survival during antibiotic exposure is a complex and multifaceted phenomenon. On top of antibiotic resistance genes, biofilm formation, and persister tolerance, bacterial membrane vesicles (MVs) provide a layer of protection that has been largely overlooked. MVs are spherical nanoparticles composed of lipid membranes and are common to Gram-positive and Gram-negative bacteria.

Deletion of a previously uncharacterized lipoprotein lirL confers resistance to an inhibitor of type II signal peptidase in .

is a clinically important, predominantly health care-associated gram-negative bacterium with high rates of emerging resistance worldwide. Given the urgent need for novel antibacterial therapies against , we focused on inhibiting lipoprotein biosynthesis, a pathway that is essential for envelope biogenesis in gram-negative bacteria. The natural product globomycin, which inhibits the essential type II signal peptidase prolipoprotein signal peptidase (LspA), is ineffective against wild-type clinical isolates due to its poor penetration through the outer membrane.

Monitoring Mitochondrial Perturbations During Infection.

Mitochondria are pivotal organelles in the cell that regulate a myriad of cellular functions, which eventually govern cellular physiology and homeostasis. Intriguingly, microbial infection is known to trigger morphological and functional alterations of mitochondria. In fact, a number of bacteria and viruses have been reported to hijack mitochondrial functions including cell death induction and regulation of immune signaling to evade detection, promote their intracellular growth and subsequent dissemination.

Sialic acid diversity in the human gut: Molecular impacts and tools for future discovery.

Sialic acids are a family of structurally related sugars that are prevalent in mucosal surfaces, including the human intestine. In the gut, sialic acids have diverse biological roles at the interface of the host epithelium and the microbiota. N-acetylneuraminic acid (Neu5Ac), the best studied sialic acid, is a nutrient source for bacteria and, when displayed on the cell surface, a binding site for host immune factors, viruses, and bacterial toxins.

Secretes a Bioactive Lipid That Triggers Inflammatory Signaling and Cell Death.

is a highly pathogenic Gram-negative bacterium that causes severe infections with very high fatality rates. infection triggers innate as well as adaptive immunity, however, our understanding of the inflammatory factors secreted by that alarm the immune system remains limited. In this study, we report that the lab adapted and clinical strains of secrete an inflammatory bioactive factor which activates TLR2, leading to canonical IRAK4-dependent NF-κB signaling and production of pro-inflammatory cytokines interleukin (IL)-6 and IL-8 and activation of the inflammasome pathway causing pyroptotic cell death.

Host immunity and cellular responses to bacterial outer membrane vesicles.

All Gram-negative bacteria produce outer membrane vesicles (OMVs) which are minute spherical structures emanating from the bacterial outer membrane. OMVs are primarily enriched in lipopolysaccharide (LPS) and phospholipids, as well as outer membrane and periplasmic proteins. Recent research has provided convincing evidence for their role in multiple aspects of bacterial physiology and their interaction with vertebrate host cells.

Shigella ubiquitin ligase IpaH7.8 targets gasdermin D for degradation to prevent pyroptosis and enable infection.

The pore-forming protein gasdermin D (GSDMD) executes lytic cell death called pyroptosis to eliminate the replicative niche of intracellular pathogens. Evolution favors pathogens that circumvent this host defense mechanism. Here, we show that the Shigella ubiquitin ligase IpaH7.

Outer membrane vesicles containing OmpA induce mitochondrial fragmentation to promote pathogenesis of Acinetobacter baumannii.

Acinetobacter baumannii is a highly antibiotic resistant Gram-negative bacterium that causes life-threatening infections in humans with a very high mortality rate. A. baumannii is an extracellular pathogen with poorly understood virulence mechanisms.

Mitochondrial Functions in Infection and Immunity.

Mitochondria have a central role in regulating a range of cellular activities and host responses upon bacterial infection. Multiple pathogens affect mitochondria dynamics and functions to influence their intracellular survival or evade host immunity. On the other side, major host responses elicited against infections are directly dependent on mitochondrial functions, thus placing mitochondria centrally in maintaining homeostasis upon infection.

Publisher Correction: Definitions and guidelines for research on antibiotic persistence.

In Figure 2b, the minimal duration for killing (MDK) 99% of tolerant cells was erroneously labelled as MDK99.99 instead of MDK99. This has now been corrected in all versions of the Review.

Definitions and guidelines for research on antibiotic persistence.

Increasing concerns about the rising rates of antibiotic therapy failure and advances in single-cell analyses have inspired a surge of research into antibiotic persistence. Bacterial persister cells represent a subpopulation of cells that can survive intensive antibiotic treatment without being resistant. Several approaches have emerged to define and measure persistence, and it is now time to agree on the basic definition of persistence and its relation to the other mechanisms by which bacteria survive exposure to bactericidal antibiotic treatments, such as antibiotic resistance, heteroresistance or tolerance.

Optimized arylomycins are a new class of Gram-negative antibiotics.

Multidrug-resistant bacteria are spreading at alarming rates, and despite extensive efforts no new class of antibiotic with activity against Gram-negative bacteria has been approved in over fifty years. Natural products and their derivatives have a key role in combating Gram-negative pathogens. Here we report chemical optimization of the arylomycins-a class of natural products with weak activity and limited spectrum-to obtain G0775, a molecule with potent, broad-spectrum activity against Gram-negative bacteria.

Structural basis for dual-mode inhibition of the ABC transporter MsbA.

The movement of core-lipopolysaccharide across the inner membrane of Gram-negative bacteria is catalysed by an essential ATP-binding cassette transporter, MsbA. Recent structures of MsbA and related transporters have provided insights into the molecular basis of active lipid transport; however, structural information about their pharmacological modulation remains limited. Here we report the 2.