scholarly journals Cyclohexyl-griselimycin is active against Mycobacterium abscessus in mice

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 .

scholarly journals Epetraborole is Active against Mycobacterium abscessus

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.

scholarly journals F11-Mediated Inhibition of RhoA Signalling Enhances the Spread of Vaccinia Virus In Vitro and In Vivo in an Intranasal Mouse Model of Infection

PLoS ONE ◽  
2009 ◽  
Vol 4 (12) ◽  
pp. e8506 ◽  
Author(s):  
João V. Cordeiro ◽  
Susana Guerra ◽  
Yoshiki Arakawa ◽  
Mark P. Dodding ◽  
Mariano Esteban ◽  
...  
Keyword(s):  
Mouse Model ◽  
Vaccinia Virus ◽  
Mouse Model Of Infection

scholarly journals Developing an antibiotic effective against multi-drug resistant bacteria.

2014 ◽  
Vol 70 (a1) ◽  
pp. C714-C714
Author(s):  
Calvin Steussy ◽  
Cynthia Stauffacher ◽  
Mark Lipton ◽  
Mohamed Seleem
Keyword(s):  
Pathogenic Bacteria ◽  
Modern Medicine ◽  
In Vivo Studies ◽  
Resistant Bacteria ◽  
Drug Resistant ◽  
Lead Compound ◽  
Drug Resistant Bacteria ◽  
Coa Reductase

The emergence of multi-drug resistant pathogenic bacteria is one of the great challenges to modern medicine. The gram positive cocci Methicillin Resistant Staphylococcus aureus (MRSA) and Vancomycin Resistant Enterococcus faecalis (VRE) are two particularly virulent examples. In vivo studies have shown that the eukaryotic like 'mevalonate' isoprenoid pathway used by these pathogenic cocci is essential to their growth and virulence [1]. Our structures of HMG-CoA reductase (HMGR) from P. mevalonii demonstrated that the bacterial enzymes are structurally distinct from the human enzymes allowing for specific antibacterial activity [2]. High throughput in vitro screening against bacterial HMGR at the Southern Research Center, Birmingham, AL uncovered a lead compound with an IC50 of 80 µM with a competitive mode of action. Our x-ray crystal structures of HMGR from E. faecalis complexed with the lead compound and its variations have informed the synthesis of new inhibitors that have improved the IC50 to 5 µM [3]. Studies of this compound show it to be active against both MRSA and VRE in culture, effective against these bacteria in biofilms, and efficacious in a model system of eukaryotic infection. Structures and kinetics of these compounds will be presented and future directions discussed.

scholarly journals Potential of Novel Antimicrobial Peptide P3 from Bovine Erythrocytes and Its Analogs To Disrupt Bacterial MembranesIn Vitroand Display Activity against Drug-Resistant Bacteria in a Mouse Model

2015 ◽  
Vol 59 (5) ◽  
pp. 2835-2841 ◽  
Author(s):  
Qinghua Zhang ◽  
Yanzhao Xu ◽  
Qing Wang ◽  
Bolin Hang ◽  
Yawei Sun ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Body Weight ◽  
Mouse Model ◽  
Antimicrobial Activities ◽  
Resistant Bacteria ◽  
Drug Resistant ◽  
Drug Resistant Bacteria ◽  
Resistant Strains ◽  
Bovine Erythrocytes

ABSTRACTWith the emergence of many antibiotic-resistant strains worldwide, antimicrobial peptides (AMPs) are being evaluated as promising alternatives to conventional antibiotics. P3, a novel hemoglobin peptide derived from bovine erythrocytes, exhibited modest antimicrobial activityin vitro. We evaluated the antimicrobial activities of P3 and an analog, JH-3, bothin vitroandin vivo. The MICs of P3 and JH-3 ranged from 3.125 μg/ml to 50 μg/ml when a wide spectrum of bacteria was tested, including multidrug-resistant strains. P3 killed bacteria within 30 min by disrupting the bacterial cytoplasmic membrane and disturbing the intracellular calcium balance. Circular dichroism (CD) spectrometry showed that P3 assumed an α-helical conformation in bacterial lipid membranes, which was indispensable for antimicrobial activity. Importantly, the 50% lethal dose (LD50) of JH-3 was 180 mg/kg of mouse body weight after intraperitoneal (i.p.) injection, and no death was observed at any dose up to 240 mg/kg body weight following subcutaneous (s.c.) injection. Furthermore, JH-3 significantly decreased the bacterial count and rescued infected mice in a model of mouse bacteremia. In conclusion, P3 and an analog exhibited potent antimicrobial activities and relatively low toxicities in a mouse model, indicating that they may be useful for treating infections caused by drug-resistant bacteria.

scholarly journals In Vitro Activity of New Tetracycline Analogs Omadacycline and Eravacycline against Drug-Resistant Clinical Isolates of Mycobacterium abscessus

2019 ◽  
Vol 63 (6) ◽  
Author(s):  
Amit Kaushik ◽  
Nicole C. Ammerman ◽  
Olumide Martins ◽  
Nicole M. Parrish ◽  
Eric L. Nuermberger
Keyword(s):  
Salvage Therapy ◽  
Treatment Options ◽  
Oral Formulation ◽  
Mycobacterium Abscessus ◽  
Clinical Isolates ◽  
Drug Resistant ◽  
In Vitro Activity ◽  
Content Type ◽  
New Treatment

ABSTRACT Tigecycline is used in multidrug regimens for salvage therapy of Mycobacterium abscessus infections but is often poorly tolerated and has no oral formulation. Here, we report similar in vitro activity of two newly approved tetracycline analogs, omadacycline and eravacycline, against 28 drug-resistant clinical isolates of M. abscessus complex. Since omadacycline and eravacycline appear to be better tolerated than tigecycline and since omadacycline is also formulated for oral dosing, these tetracycline analogs may represent new treatment options for M. abscessus infections.

Genetic manipulation of Neospora caninum to express the bradyzoite-specific protein NcSAG4 in tachyzoites

Parasitology ◽  
2011 ◽  
Vol 138 (4) ◽  
pp. 472-480 ◽  
Author(s):  
V. MARUGÁN-HERNÁNDEZ ◽  
L. M. ORTEGA-MORA ◽  
A. AGUADO-MARTÍNEZ ◽  
G. ÁLVAREZ-GARCÍA
Keyword(s):  
Mouse Model ◽  
Genetic Manipulation ◽  
Neospora Caninum ◽  
Constitutive Expression ◽  
Chronic Phase ◽  
Specific Protein ◽  
Host Cells ◽  
Mouse Model Of Infection ◽  
Transgenic Strains

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.

scholarly journals In vitro selection predicts malaria parasite resistance to dihydroorotate dehydrogenase inhibitors in a mouse infection model

2019 ◽  
Vol 11 (521) ◽  
pp. eaav1636 ◽  
Author(s):  
Rebecca E. K. Mandt ◽  
Maria Jose Lafuente-Monasterio ◽  
Tomoyo Sakata-Kato ◽  
Madeline R. Luth ◽  
Delfina Segura ◽  
...  
Keyword(s):  
Mouse Model ◽  
In Vitro Selection ◽  
Infection Model ◽  
Drug Resistant ◽  
Dihydroorotate Dehydrogenase ◽  
Mouse Infection Model ◽  
Development Of Resistance ◽  
Mouse Infection

Resistance has developed in Plasmodium malaria parasites to every antimalarial drug in clinical use, prompting the need to characterize the pathways mediating resistance. Here, we report a framework for assessing development of resistance of Plasmodium falciparum to new antimalarial therapeutics. We investigated development of resistance by P. falciparum to the dihydroorotate dehydrogenase (DHODH) inhibitors DSM265 and DSM267 in tissue culture and in a mouse model of P. falciparum infection. We found that resistance to these drugs arose rapidly both in vitro and in vivo. We identified 13 point mutations mediating resistance in the parasite DHODH in vitro that overlapped with the DHODH mutations that arose in the mouse infection model. Mutations in DHODH conferred increased resistance (ranging from 2- to ~400-fold) to DHODH inhibitors in P. falciparum in vitro and in vivo. We further demonstrated that the drug-resistant parasites carrying the C276Y mutation had mitochondrial energetics comparable to the wild-type parasite and also retained their fitness in competitive growth experiments. Our data suggest that in vitro selection of drug-resistant P. falciparum can predict development of resistance in a mouse model of malaria infection.

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

2020 ◽  
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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