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New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections.

ABSTRACT: Toxoplasma gondii, the most common parasitic infection of human brain and eye, persists across lifetimes, can progressively damage sight, and is currently incurable. New, curative medicines are needed urgently. Herein, we develop novel models to facilitate drug development: EGS strain T. gondii forms cysts in vitro that induce oocysts in cats, the gold standard criterion for cysts. These cysts highly express cytochrome b. Using these models, we envisioned, and then created, novel 4-(1H)-quinolone scaffolds that target the cytochrome bc1 complex Qi site, of which, a substituted 5,6,7,8-tetrahydroquinolin-4-one inhibits active infection (IC50, 30?nM) and cysts (IC50, 4??M) in vitro, and in vivo (25?mg/kg), and drug resistant Plasmodium falciparum (IC50, <30?nM), with clinically relevant synergy. Mutant yeast and co-crystallographic studies demonstrate binding to the bc1 complex Qi site. Our results have direct impact on improving outcomes for those with toxoplasmosis, malaria, and ~2 billion persons chronically infected with encysted bradyzoites.

SUBMITTER: McPhillie M

PROVIDER: S-EPMC4944145 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections.

McPhillie Martin M Zhou Ying Y El Bissati Kamal K Dubey Jitender J Lorenzi Hernan H Capper Michael M Lukens Amanda K AK Hickman Mark M Muench Stephen S Verma Shiv Kumar SK Weber Christopher R CR Wheeler Kelsey K Gordon James J Sanders Justin J Moulton Hong H Wang Kai K Kim Taek-Kyun TK He Yuqing Y Santos Tatiana T Woods Stuart S Lee Patty P Donkin David D Kim Eric E Fraczek Laura L Lykins Joseph J Esaa Farida F Alibana-Clouser Fatima F Dovgin Sarah S Weiss Louis L Brasseur Gael G Wirth Dyann D Kent Michael M Hood Leroy L Meunieur Brigitte B Roberts Craig W CW Hasnain S Samar SS Antonyuk Svetlana V SV Fishwick Colin C McLeod Rima R

Scientific reports 20160714

Toxoplasma gondii, the most common parasitic infection of human brain and eye, persists across lifetimes, can progressively damage sight, and is currently incurable. New, curative medicines are needed urgently. Herein, we develop novel models to facilitate drug development: EGS strain T. gondii forms cysts in vitro that induce oocysts in cats, the gold standard criterion for cysts. These cysts highly express cytochrome b. Using these models, we envisioned, and then created, novel 4-(1H)-quinolon ...[more]

PMID: 27412848

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Project description:RationaleCardiorespiratory insufficiency (CRI) is a term applied to the manifestations of loss of normal cardiorespiratory reserve and portends a bad outcome. CRI occurs commonly in hospitalized patients, but its risk escalation patterns are unexplored.ObjectivesTo describe the dynamic and personal character of CRI risk evolution observed through continuous vital sign monitoring of individual step-down unit patients.MethodsUsing a machine learning model, we estimated risk trends for CRI (defined as exceedance of vital sign stability thresholds) for each of 1,971 admissions (1,880 unique patients) to a 24-bed adult surgical trauma step-down unit at an urban teaching hospital in Pittsburgh, Pennsylvania using continuously recorded vital signs from standard bedside monitors. We compared and contrasted risk trends during initial 4-hour periods after step-down unit admission, and again during the 4 hours immediately before the CRI event, between cases (ever had a CRI) and control subjects (never had a CRI). We further explored heterogeneity of risk escalation patterns during the 4 hours before CRI among cases, comparing personalized to nonpersonalized risk.Measurements and main resultsEstimated risk was significantly higher for cases (918) than control subjects (1,053; P ≤ 0.001) during the initial 4-hour stable periods. Among cases, the aggregated nonpersonalized risk trend increased 2 hours before the CRI, whereas the personalized risk trend became significantly different from control subjects 90 minutes ahead. We further discovered several unique phenotypes of risk escalation patterns among cases for nonpersonalized (14.6% persistently high risk, 18.6% early onset, 66.8% late onset) and personalized risk (7.7% persistently high risk, 8.9% early onset, 83.4% late onset).ConclusionsInsights from this proof-of-concept analysis may guide design of dynamic and personalized monitoring systems that predict CRI, taking into account the triage and real-time monitoring utility of vital signs. These monitoring systems may prove useful in the dynamic allocation of technological and clinical personnel resources in acute care hospitals.

Dataset Information

New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections.

Publications

New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections.

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