Synergy of ciprofloxacin and azlocillin in vitro and in a neutropenic mouse model of infection

SUMMARYNeospora caninum is an apicomplexan parasite and the aetiological agent of bovine neosporosis, one of the main causes of reproductive failure worldwide. We have generated 2 independent transgenic knock-in clones, Nc-1SAG4c1.1 and Nc-1SAG4c2.1, that express the bradyzoite stage-specific protein NcSAG4 in the tachyzoite stage. These clones have similar growth rates in vitro as the wild-type (WT) strain Nc-1. Studies in a cerebral mouse model of infection revealed a slightly lower rate of detection of the transgenic strains in brains during the chronic phase of infection. However, a pregnant mouse model of infection revealed a reduction in the virulence of the Nc-1SAG4c1.1 strain despite the same tachyzoite expression of NcSAG4 and a similar anti-NcSAG4 response displayed by mice inoculated with Nc-1 SAG4c1.1 or Nc-1 SAG4c2.1 parasites. This behaviour may be related to the reduced ability of the Nc-1SAG4c1.1 parasites to invade host cells, which was observed in in vitro assays. The apparent reduction in persistence and the high growth rate of the transgenic strains, together with their constitutive expression of the protein NcSAG4, may be useful features for future immunoprophylaxis trials based on a safe live attenuated vaccine.

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Epetraborole is Active against Mycobacterium abscessus

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01156-21 ◽

2021 ◽

Author(s):

Uday S. Ganapathy ◽

Martin Gengenbacher ◽

Thomas Dick

Keyword(s):

Mouse Model ◽

Lung Disease ◽

Trna Synthetase ◽

Mycobacterium Abscessus ◽

Gram Negative ◽

Lead Compounds ◽

New Class ◽

Mouse Model Of Infection ◽

Clinical Candidate

Benzoxaboroles are a new class of leucyl-tRNA synthetase inhibitors. We recently reported that the antitubercular 4-halogenated benzoxaboroles are active against Mycobacterium abscessus . Here, we find that the non-halogenated benzoxaborole epetraborole, a clinical candidate developed for Gram negative infections, is also active against M. abscessus in vitro and in a mouse model of infection. This expands the repertoire of advanced lead compounds for the discovery of a benzoxaborole-based candidate to treat M. abscessus lung disease.

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Cyclohexyl-griselimycin is active against Mycobacterium abscessus in mice

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01400-21 ◽

2021 ◽

Author(s):

Wassihun Wedajo Aragaw ◽

Christine Roubert ◽

Evelyne Fontaine ◽

Sophie Lagrange ◽

Matthew D. Zimmerman ◽

...

Keyword(s):

Mouse Model ◽

Fast Track ◽

Mycobacterium Abscessus ◽

Drug Resistant ◽

Lead Compound ◽

Drug Pipeline ◽

Mouse Model Of Infection ◽

Novel Antibiotics ◽

Chemical Matter

Cyclohexyl-griselimycin is a preclinical candidate for tuberculosis (TB). Here, we show that this oral cyclodepsipeptide is also active against the intrinsically drug resistant non-tuberculous mycobacterium Mycobacterium abscessus in vitro and in a mouse model of infection. This adds a novel advanced lead compound to the M. abscessus drug pipeline and supports a strategy of screening chemical matter generated in TB drug discovery efforts to fast track the discovery of novel antibiotics against M. abscessus .

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Treating Influenza and SARS-CoV-2 via mRNA-encoded Cas13a

10.1101/2020.04.24.060418 ◽

2020 ◽

Cited By ~ 2

Author(s):

Emmeline L. Blanchard ◽

Daryll Vanover ◽

Swapnil Subhash Bawage ◽

Pooja Munnilal Tiwari ◽

Laura Rotolo ◽

...

Keyword(s):

Influenza Virus ◽

Mouse Model ◽

Post Infection ◽

Cytopathic Effect ◽

Respiratory Infections ◽

Synthetic Mrna ◽

Mouse Model Of Infection ◽

Over Time

ABSTRACTHere, Cas13a has been used to target and mitigate influenza virus A (IAV) and SARS-CoV-2 using a synthetic mRNA-based platform. CRISPR RNAs (crRNA) against PB1 and highly conserved regions of PB2 were screened in conjunction with mRNA-encoded Cas13a. Screens were designed such that only guides that decreased influenza RNA levels in a Cas13-mediated fashion, were valid. Cas13a mRNA and validated guides, delivered post-infection, simulating treatment, were tested in combination and across multiplicities of infection. Their function was also characterized over time. Similar screens were performed for guides against SARS-CoV-2, yielding multiple guides that significantly impacted cytopathic effect. Last, the approach was utilized in vivo, demonstrating the ability to degrade influenza RNA in a mouse model of infection, using polymer-formulated, nebulizer-based mRNA delivery. Our findings demonstrate the applicability of Cas13a in mitigating respiratory infections both in vitro and in a mouse model, paving the way for future therapeutic use.

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In Vivo Investigations of Selected Diamidine Compounds against Trypanosoma evansi Using a Mouse Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00422-09 ◽

2009 ◽

Vol 53 (12) ◽

pp. 5074-5079 ◽

Cited By ~ 7

Author(s):

Kirsten Gillingwater ◽

Arvind Kumar ◽

Mariappan Anbazhagan ◽

David W. Boykin ◽

Richard R. Tidwell ◽

...

Keyword(s):

Mouse Model ◽

Trypanosoma Evansi ◽

Chemotherapeutic Agents ◽

Control Measures ◽

Lead Compounds ◽

Protozoan Infection ◽

Drug Doses ◽

Mouse Model Of Infection

ABSTRACT Surra is an animal pathogenic protozoan infection, caused by Trypanosoma evansi, that develops into a fatal wasting disease. Control measures rely on diagnosis and treatment. However, with the continuous emergence of drug resistance, this tactic is failing, and the pressing need for new chemotherapeutic agents is becoming critical. With the introduction of novel aromatic diamidines, a new category of antitrypanosomal drugs was discovered. Nevertheless, their efficacy within a T. evansi-infected mouse model was not known. In total, 30 compounds previously selected based on their in vitro activity were tested in a T. evansi mouse model of infection. Six of the compounds were capable of curing T. evansi-infected mice at drug doses as low as 0.5 and 0.25 mg/kg of body weight administered for 4 consecutive days, and they were more effective than the standard drugs suramin, diminazene, and quinapyramine. After all selection criteria were applied, three diamidine compounds (DB 75, DB 867, and DB 1192) qualified as lead compounds and were considered to have the potential to act as preclinical candidates against T. evansi infection.

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Type IV Pili PromoteClostridium difficileAdherence and Persistence in a Mouse Model of Infection

Infection and Immunity ◽

10.1128/iai.00943-17 ◽

2018 ◽

Vol 86 (5) ◽

Cited By ~ 20

Author(s):

Robert W. McKee ◽

Naira Aleksanyan ◽

Elizabeth M. Garrett ◽

Rita Tamayo

Keyword(s):

Epithelial Cells ◽

Mouse Model ◽

Type Iv Pili ◽

Host Cells ◽

Content Type ◽

Type Iv ◽

Flagellum Biosynthesis ◽

Mouse Model Of Infection ◽

Null Mutants

ABSTRACTCyclic diguanylate (c-di-GMP) is a second messenger that regulates the transition from motile to sessile lifestyles in numerous bacteria and controls virulence factor production in a variety of pathogens. InClostridium difficile, c-di-GMP negatively regulates flagellum biosynthesis and swimming motility and promotes the production of type IV pili (TFP), biofilm formation, and surface motilityin vitro. Flagella have been identified as colonization factors inC. difficile, but the role of TFP in adherence to host cells and in colonization of the mammalian gut is unknown. Here we show that c-di-GMP promotes adherence to epithelial cellsin vitro, which can be partly attributed to the loss of flagella. Using TFP-null mutants, we demonstrate that adherence to epithelial cells is partially mediated by TFP and that this TFP-mediated adherence requires c-di-GMP regulation. In a mouse model of colonization, the TFP-null mutants initially colonized the intestine as well as the parental strain but were cleared more quickly. Moreover, compared to the parent strain,C. difficilestrains lacking TFP were particularly deficient in association with the cecal mucosa. Together these data indicate that TFP and their positive regulation by c-di-GMP promote attachment ofC. difficileto the intestinal epithelium and contribute to persistence ofC. difficilein the host intestine.

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Repurposing Pyramax® for the Treatment of Ebola Virus Disease: Additivity of the Lysosomotropic Pyronaridine and Non-Lysosomotropic Artesunate

10.1101/2020.04.25.061333 ◽

2020 ◽

Cited By ~ 1

Author(s):

Thomas R. Lane ◽

Julie Dyall ◽

Luke Mercer ◽

Caleb Goodin ◽

Daniel H. Foil ◽

...

Keyword(s):

Machine Learning ◽

Mouse Model ◽

Viral Entry ◽

Ebola Virus ◽

Virus Disease ◽

Combination Effect ◽

Combination Product ◽

Machine Learning Model ◽

Mouse Model Of Infection

AbstractWe have recently identified three molecules (tilorone, quinacrine and pyronaridine tetraphosphate) which all demonstrated efficacy in the mouse model of infection with mouse-adapted Ebola virus (EBOV) model of disease and had similar in vitro inhibition of an Ebola pseudovirus (VSV-EBOV-GP), suggesting they interfere with viral entry. Using a machine learning model to predict lysosomotropism these compounds were evaluated for their ability to inhibit via a lysosomotropic mechanism in vitro. We now demonstrate in vitro that pyronaridine tetraphosphate is an inhibitor of Lysotracker accumulation in lysosomes (IC50 = 0.56 μM). Further, we evaluated synergy between pyronaridine and artesunate (Pyramax®), which are used in combination to treat malaria. Artesunate was not found to have lysosomotropic activity in vitro and the combination effect on EBOV inhibition was shown to be additive. Pyramax® may represent a unique example of the repurposing of a combination product for another disease.

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