An O-Specific Polysaccharide Shigella flexneri 3a Conjugate Vaccine is Immunogenic and Protective against Virulent Keratoconjunctival Challenge in Guinea Pigs.

Shigella infection is a major cause of diarrhea, cognitive and physical stunting, and death in young children in resource-limited settings. A vaccine that is protective against shigellosis is needed. Immune responses that target the O-specific polysaccharide (OSP) of Shigella spp.

Development of a Shigella conjugate vaccine targeting Shigella flexneri 6 that is immunogenic and provides protection against virulent challenge.

Immunity protective against shigella infection targets the bacterial O-specific polysaccharide (OSP) component of lipopolysaccharide. A multivalent shigella vaccine would ideally target the most common global Shigella species and serotypes such as Shigella flexneri 2a, S. flexneri 3a, S.

C-C Motif Ligand 7 and C-C Motif Chemokine Receptor 3 Dysregulation in Patients With Scrub Typhus and Association With Mortality.

Background: Scrub typhus, caused by Orientia tsutsugamushi, involves infiltration of a mixture of perivascular lymphocytes and macrophages into affected organs. We investigated if this is characterized by chemokine dysregulation.

Methods: mRNA expression of chemokines and receptors was screened in whole blood by cDNA microarray in a subgroup of patients and controls.

Canonical notch activation in patients with scrub typhus: association with organ dysfunction and poor outcome.

Purpose: The mechanisms that control inflammation in scrub typhus are not fully elucidated. The Notch pathways are important regulators of inflammation and infection, but have not been investigated in scrub typhus.

Methods: Plasma levels of the canonical Notch ligand Delta-like protein 1 (DLL1) were measured by enzyme immunoassay and RNA expression of the Notch receptors (NOTCH1, NOTCH2 and NOTCH4) in whole blood was analyzed by real-time PCR in patients with scrub typhus (n = 129), in patients with similar febrile illness without O.

A Potent and Narrow-Spectrum Antibacterial against Infection.

is an anaerobic Gram-positive bacterium that colonizes the gut of patients treated with broad-spectrum antibiotics. The normal gut microflora prevents . colonization; however, dysbiosis by treatment with broad-spectrum antibiotics causes recurrent .

A dual-action antibiotic that kills vegetative cells and inhibits spore germination.

infection (CDI) is the most lethal of the five CDC urgent public health treats, resulting in 12,800 annual deaths in the United States alone [ (2019), www.cdc.gov/DrugResistance/Biggest-Threats.

Performance assessment and economic analysis of a human Liver-Chip for predictive toxicology.

Background: Conventional preclinical models often miss drug toxicities, meaning the harm these drugs pose to humans is only realized in clinical trials or when they make it to market. This has caused the pharmaceutical industry to waste considerable time and resources developing drugs destined to fail. Organ-on-a-Chip technology has the potential improve success in drug development pipelines, as it can recapitulate organ-level pathophysiology and clinical responses; however, systematic and quantitative evaluations of Organ-Chips' predictive value have not yet been reported.

Structure-Activity Relationship for the Picolinamide Antibacterials that Selectively Target .

is a leading health threat. This pathogen initiates intestinal infections during gut microbiota dysbiosis caused by oral administration of antibiotics. is difficult to eradicate due to its ability to form spores, which are not susceptible to antibiotics.

Secreted Wnt antagonists in scrub typhus.

Background: The mechanisms that control local and systemic inflammation in scrub typhus have only been partially elucidated. The wingless (Wnt) signaling pathways are emerging as important regulators of inflammation and infection, but have not been investigated in scrub typhus.

Methodology/principal Findings: Plasma levels of secreted Wnt antagonists (i.

Discovery of a Potent Picolinamide Antibacterial Active against .

A major challenge for chemotherapy of bacterial infections is perturbation of the intestinal microbiota. is a Gram-positive bacterium of the gut that can thrive under this circumstance. Its production of dormant and antibiotic-impervious spores results in chronic disruption of normal gut flora and debilitating diarrhea and intestinal infection.

Synthetic Antimicrobial Peptide Tuning Permits Membrane Disruption and Interpeptide Synergy.

The ribosomally produced antimicrobial peptides of bacteria (bacteriocins) represent an unexplored source of membrane-active antibiotics. We designed a library of linear peptides from a circular bacteriocin and show that pore-formation dynamics in bacterial membranes are tunable via selective amino acid substitution. We observed antibacterial interpeptide synergy indicating that fundamentally altering interactions with the membrane enables synergy.

Exploration of the Structural Space in 4(3)-Quinazolinone Antibacterials.

We report herein the syntheses of 79 derivatives of the 4(3)-quinazolinones and their structure-activity relationship (SAR) against methicillin-resistant (MRSA). Twenty one analogs were further evaluated in in vitro assays. Subsequent investigation of the pharmacokinetic properties singled out compound (()-3-(5-carboxy-2-fluorophenyl)-2-(4-cyanostyryl)quinazolin-4(3)-one) for further study.

Structure-Activity Relationship for the Oxadiazole Class of Antibacterials.

A structure-activity relationship (SAR) for the oxadiazole class of antibacterials was evaluated by syntheses of 72 analogs and determination of the minimal-inhibitory concentrations (MICs) against the ESKAPE panel of bacteria. Selected compounds were further evaluated for toxicity, plasma protein binding, pharmacokinetics (PK), and a mouse model of methicillin-resistant (MRSA) infection. Oxadiazole shows potent antibacterial activity, exhibits low clearance, a high volume of distribution, and 41% oral bioavailability, and shows efficacy in mouse models of MRSA infection.

Serum siderocalin levels in patients with tuberculosis and HIV infection.

Objectives: Mycobacterium tuberculosis produces high-affinity siderophores that play essential roles in iron acquisition and tuberculosis (TB) pathogenesis. In response, host cells secrete a siderophore-binding protein, siderocalin, to limit the bacteria's access to iron. The objective of the present study was to evaluate the levels of siderocalin in patients with TB with or without HIV infection compared to controls.

The Quinazolinone Allosteric Inhibitor of PBP 2a Synergizes with Piperacillin and Tazobactam against Methicillin-Resistant Staphylococcus aureus.

The quinazolinones are a new class of antibacterials with efficacy against methicillin-resistant (MRSA). The quinazolinones target cell wall biosynthesis and have a unique mechanism of action by binding to the allosteric site of penicillin-binding protein 2a (PBP 2a). We investigated the potential for synergism of a lead quinazolinone with several antibiotics of different classes using checkerboard and time-kill assays.

The oxadiazole antibacterials.

The oxadiazoles are a class of antibacterials discovered by in silico docking and scoring of compounds against the X-ray structure of a penicillin-binding protein. These antibacterials exhibit activity against Gram-positive bacteria, including against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). They show in vivo efficacy in murine models of peritonitis/sepsis and neutropenic thigh MRSA infection.

In Vitro and In Vivo Synergy of the Oxadiazole Class of Antibacterials with β-Lactams.

The oxadiazole antibacterials target the bacterial cell wall and are bactericidal. We investigated the synergism of ND-421 with the commonly used β-lactams and non-β-lactam antibiotics by the checkerboard method and by time-kill assays. ND-421 synergizes well with β-lactam antibiotics, and it also exhibits a long postantibiotic effect (4.

Elusive treatment for human rhinosporidiosis.

Objectives: The aim of this study was to clarify the contentious taxonomic classification of Rhinosporidium seeberi, the cause of human rhinosporidiosis, which may have treatment implications.

Methods: PCR was used to amplify the internal transcribed spacer (ITS)-2 region from the genomic DNA of the aetiological agent obtained from a sample of human rhinosporidiosis lesions. The amplicon was sequenced and the organism identified using the Basic Local Alignment Search Tools (BLAST).

Prevalence of Toxin Genes among the Clinical Isolates of Staphylococcus aureus and its Clinical Impact.

Introduction: Staphylococcus aureus (S. aureus) causes a variety of infections, ranging from a mild skin infection to blood stream infections and deep seated infections. As Stapylococcus aureus bacteremia (SAB) has the tendency to cause endovascular and metastatic infections, complications can occur at almost all sites of the body.

Molecular epidemiology and genetic diversity of Orientia tsutsugamushi from patients with scrub typhus in 3 regions of India.

Scrub typhus, an acute febrile illness that is widespread in the Asia-Pacific region, is caused by the bacterium Orientia tsutsugamushi, which displays high levels of antigenic variation. We conducted an investigation to identify the circulating genotypes of O. tsutsugamushi in 3 scrub typhus-endemic geographic regions of India: South India, Northern India, and Northeast India.

Diagnosis of scrub typhus.

Scrub typhus is an acute febrile illness that, if untreated, can result in considerable morbidity and mortality. One of the primary reasons for delays in the treatment of this potentially fatal infection is the difficulty in diagnosing the condition. Diagnosis is often complicated because of the combination of non-specific symptoms that overlap with other infections commonly found in endemic areas and the poor available diagnostics.

Increased endothelial and macrophage markers are associated with disease severity and mortality in scrub typhus.

Objectives: Scrub typhus is endemic in the Asia-Pacific region. Mortality is high even with treatment, and further knowledge of the immune response during this infection is needed. This study was aimed at comparing plasma levels of monocyte/macrophage and endothelial related inflammatory markers in patients and controls in South India and to explore a possible correlation to disease severity and clinical outcome.