Synthesis of the 5/5-spiroindimicin alkaloids: development of a general synthetic approach and biological investigations.

We describe the development of a unified synthetic strategy for the preparation of all known 5/5-spirocyclic spiroindimicin (SPM) alkaloids, namely spiroindimicins B-G. The present synthetic route relies on four fundamental transformations: Grignard-based fragment coupling between halogenated pyrrolemetal and isatin partners, Suzuki coupling to generate a triaryl scaffold encompassing all requisite skeletal atoms of the natural products, Lewis acid-mediated spirocyclization to construct the 5/5-spirocyclic core, and chemoselective lactam reduction. The developed syntheses are step-economic (6-7 steps from commercial materials), scalable, and amenable to analogue synthesis.

Using machine learning to dissect host kinases required for Leishmania internalization and development.

The Leishmania life cycle alternates between promastigotes, found in the sandfly, and amastigotes, found in mammals. When an infected sandfly bites a host, promastigotes are engulfed by phagocytes (i.e.

A Multi-Color Immunofluorescence Assay to Distinguish Intracellular From External Parasites.

Leishmaniasis, a neglected tropical disease, is caused by the intracellular protozoan parasite . Upon its transmission through a sandfly bite, binds and enters host phagocytic cells, ultimately resulting in a cutaneous or visceral form of the disease. The limited therapeutics available for leishmaniasis, in combination with this parasite's techniques to evade the host immune system, call for exploring various methods to target this infection.

Using machine learning to dissect host kinases required for internalization and development.

The life cycle alternates between promastigotes, found in the sandfly, and amastigotes, found in mammals. When an infected sandfly bites a host, promastigotes are engulfed by phagocytes (., neutrophils, dendritic cells, and macrophages) to establish infection.

MAPK/ERK activation in macrophages promotes Leishmania internalization and pathogenesis.

The obligate intracellular parasite Leishmania binds several receptors to trigger uptake by phagocytic cells, ultimately resulting in visceral or cutaneous leishmaniasis. A series of signaling pathways in host cells, which are critical for establishment and persistence of infection, are activated during Leishmania internalization. Thus, preventing Leishmania uptake by phagocytes could be a novel therapeutic strategy for leishmaniasis.

Toxoplasma replication is inhibited by MMV676477 without development of resistance.

Protozoan parasites cause life-threatening infections in both humans and animals, including agriculturally significant livestock. Available treatments are typically narrow spectrum and are complicated by drug toxicity and the development of resistant parasites. Protozoan tubulin is an attractive target for the development of broad-spectrum antimitotic agents.

Cutaneous infections in the United States: defining strains through endemic human pediatric cases in northern Texas.

Unlabelled: Over a 6-month span, three patients under 5 years old with cutaneous leishmaniasis presented to the Pediatric Infectious Diseases Clinic at the University of Texas Southwestern Medical Center/Children's Health Dallas. None had traveled outside of northern Texas/southern Oklahoma; all had infections confirmed by PCR. We provide case descriptions and images to increase the awareness of this disease among United States (US) physicians and scientists.

Cutaneous Infections in the United States: Defining Strains Through Endemic Human Pediatric Cases in Northern Texas.

Over a six-month span, three patients under five years old with cutaneous leishmaniasis presented to the Pediatric Infectious Diseases Clinic at the University of Texas Southwestern Medical Center/Children's Health Dallas. None had traveled outside of the United States (US); all had confirmed infections by PCR. We provide case descriptions and images to increase the awareness of this disease among US physicians and scientists.

Src- and Abl-family kinases activate spleen tyrosine kinase to maximize phagocytosis and Leishmania infection.

Leishmania spp. are obligate intracellular parasites that must be internalized by phagocytic cells to evade immune responses and cause disease. The uptake of both Leishmania promastigotes (insect-stage parasites) and amastigotes (proliferative-stage parasites in humans and mice) by phagocytes is thought to be mainly host cell driven, not parasite driven.

CrkII/Abl phosphorylation cascade is critical for NLRC4 inflammasome activity and is blocked by Pseudomonas aeruginosa ExoT.

Type 3 Secretion System (T3SS) is a highly conserved virulence structure that plays an essential role in the pathogenesis of many Gram-negative pathogenic bacteria, including Pseudomonas aeruginosa. Exotoxin T (ExoT) is the only T3SS effector protein that is expressed in all T3SS-expressing P. aeruginosa strains.

Total synthesis of (+)-spiroindimicin A and congeners unveils their antiparasitic activity.

The spiroindimicins are a unique class of chlorinated indole alkaloids characterized by three heteroaromatic rings structured around a congested spirocyclic stereocenter. Here, we report the first total synthesis of (+)-spiroindimicin A, which bears a challenging C-3'/C-5''-linked spiroindolenine. We detail our initial efforts to effect a biomimetic oxidative spirocyclization from its proposed natural precursor, lynamicin D, and describe how these studies shaped our final abiotic 9-step solution to this complex alkaloid built around a key Pd-catalyzed asymmetric spirocyclization.

An Antiparasitic Compound from the Medicines for Malaria Venture Pathogen Box Promotes Tubulin Polymerization.

The few frontline antileishmanial drugs are poorly effective and toxic. To search for new drugs for this neglected tropical disease, we tested the activity of compounds in the Medicines for Malaria Venture (MMV) "Pathogen Box" against axenic amastigotes. Screening yielded six discovery antileishmanial compounds with EC values from 50 to 480 nM.

Erratum to: An Outbreak of Brucellosis: An Adult and Pediatric Case Series.

[This corrects the article DOI: 10.1093/ofid/ofz384.][This corrects the article DOI: 10.

The relative rate of kill of the MMV Malaria Box compounds provides links to the mode of antimalarial action and highlights scaffolds of medicinal chemistry interest.

Objectives: Rapid rate-of-kill (RoK) is a key parameter in the target candidate profile 1 (TCP1) for the next-generation antimalarial drugs for uncomplicated malaria, termed Single Encounter Radical Cure and Prophylaxis (SERCaP). TCP1 aims to rapidly eliminate the initial parasite burden, ideally as fast as artesunate, but minimally as fast as chloroquine. Here we explore whether the relative RoK of the Medicine for Malaria Venture (MMV) Malaria Box compounds is linked to their mode of action (MoA) and identify scaffolds of medicinal chemistry interest.

An Outbreak of Brucellosis: An Adult and Pediatric Case Series.

Background: Brucellosis is recognized as a neglected zoonotic disease and a major public health threat. The purpose of this study was to characterize epidemiological risk factors and healthcare utilization and compare clinical aspects of disease among adult and pediatric cases in North Texas.

Methods: A retrospective chart review of electronic medical records was completed at 3 large tertiary centers-Parkland Health and Hospital System, Clements University Hospital, and Children's Medical Center-between January 1, 2007 and June 1, 2017.

The Src kinases Hck, Fgr and Lyn activate Arg to facilitate IgG-mediated phagocytosis and Leishmania infection.

Leishmaniasis is a devastating disease that disfigures or kills nearly two million people each year. Establishment and persistence of infection by the obligate intracellular parasite Leishmania requires repeated uptake by macrophages and other phagocytes. Therefore, preventing uptake could be a novel therapeutic strategy for leishmaniasis.

The Abl and Arg kinases mediate distinct modes of phagocytosis and are required for maximal Leishmania infection.

Leishmania, an obligate intracellular parasite, binds several receptors to trigger engulfment by phagocytes, leading to cutaneous or visceral disease. These receptors include complement receptor 3 (CR3), used by promastigotes, and the Fc receptor (FcR), used by amastigotes. The mechanisms mediating uptake are not well understood.

Staphylococcus aureus activates type I IFN signaling in mice and humans through the Xr repeated sequences of protein A.

The activation of type I IFN signaling is a major component of host defense against viral infection, but it is not typically associated with immune responses to extracellular bacterial pathogens. Using mouse and human airway epithelial cells, we have demonstrated that Staphylococcus aureus activates type I IFN signaling, which contributes to its virulence as a respiratory pathogen. This response was dependent on the expression of protein A and, more specifically, the Xr domain, a short sequence-repeat region encoded by DNA that consists of repeated 24-bp sequences that are the basis of an internationally used epidemiological typing scheme.

Gliding motility leads to active cellular invasion by Cryptosporidium parvum sporozoites.

We examined gliding motility and cell invasion by an early-branching apicomplexan, Cryptosporidium parvum, which causes diarrheal disease in humans and animals. Real-time video microscopy demonstrated that C. parvum sporozoites undergo circular and helical gliding, two of the three stereotypical movements exhibited by Toxoplasma gondii tachyzoites.

Evidence that the cADPR signalling pathway controls calcium-mediated microneme secretion in Toxoplasma gondii.

The protozoan parasite Toxoplasma gondii relies on calcium-mediated exocytosis to secrete adhesins on to its surface where they can engage host cell receptors. Increases in intracellular calcium occur in response to Ins(1,4,5)P3 and caffeine, an agonist of ryanodine-responsive calcium-release channels. We examined lysates and microsomes of T.

Calcium-mediated protein secretion potentiates motility in Toxoplasma gondii.

Apicomplexans such as Toxoplasma gondii actively invade host cells using a unique parasite-dependent mechanism termed gliding motility. Calcium-mediated protein secretion by the parasite has been implicated in this process, but the precise role of calcium signaling in motility remains unclear. Here we used calmidazolium as a tool to stimulate intracellular calcium fluxes and found that this drug led to enhanced motility by T.