Name: a high-throughput compatible assay to evaluate drug efficacy against macrophage passaged mycobacterium tuberculosis
Uploaded: 2017-03-24T15:00:00
Description: Watch this Scientific Journal Video about A High-throughput Compatible Assay to Evaluate Drug Efficacy against Macrophage Passaged Mycobacterium tuberculosis at JoVE.com

We thank Dr. Frank Wolschendorf for access to the Cytation 3 automated imaging plate reader. This work was funded in part by NIH grant R01-AI104499 to OK. Parts of the work were performed in the UAB CFAR facilities and by the UAB CFAR Flow Cytometry Core/Joint UAB Flow Cytometry Core, which are funded by NIH/NIAID P30 AI027767 and by NIH 5P30 AR048311.

NOTA: Come M. tuberculosis mc 2 6206 è un ceppo non virulento 17, 18, tutti i lavori in questo protocollo può essere eseguita in un impianto di 2 livello di biosicurezza (BSL-2). 1. condizioni di coltura per la proteina fluorescente verde Esprimere M. tuberculosis mc 2 6206 (Mtb-GFP) NOTA: il M. tuberculosis H37Rv deriva auxotroph ceppo mc 2</...

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Qui, abbiamo descritto in dettaglio un modello di infezione Mtb alternativo adatto per test efficacia del farmaco. Questo modello tiene conto di due fattori chiave che dovrebbe essere dato più considerazione durante il processo di sviluppo TB farmaci precoce: la presenza di barriere fisiologicamente rilevanti alla penetrazione di droga e cambiamenti metabolici di Mtb durante l&#39;infezione. Mentre abbiamo già dimostrato i vantaggi del nostro modello di infezione e ha proposto la possibilità di scal...

<html> La tubercolosi (TB) rimane una grave minaccia globale la salute nonostante la disponibilità di regimi chemioterapici anti-TB per oltre 40 anni 1. Ciò è dovuto in parte al requisito per periodi lunghi di trattamento di più di 6 mesi utilizzando più combinazioni di farmaci, che porta al paziente non conformità 2. L&#39;emergere di TBC resistente ai farmaci negli ultimi anni ha ulteriormente aggravato i problemi in un campo in cui il successo dello sviluppo di farmaci clinicamente approvati è praticamente inesistente 3. Infatti, nonostante esaustivo anti-TB sviluppo di farmaci, solo un singolo farmaco è stato approvato dalla FDA per l&#39;uso clinico negli ultimi 40 anni 4. Così, le nuove generazioni di farmaci anti-TB sono urgentemente necessari per affrontare questo problema. Un problema fondamentale nella scoperta TB farmaco è la mancanza di trasferimento di successo da composti con attività in vitro all&#39;efficacia in ambito clinico= &quot;xref&quot;&gt; 5, 6, 7. Inizialmente, gli approcci target basati sono stati usati per lo screening per anti-Mtb farmaci 5, che non è riuscito a tradurre in cellule batteriche intere. Anche quando si usano le cellule Mtb, è spesso eseguita utilizzando brodo cresciuto culture, che non calcolano accuratamente l&#39;efficacia dei farmaci in vivo 8, 9. Questi problemi sono stati riconosciuti e test di screening di droga nei confronti di macrofagi contenenti Mtb o latente Mtb sono state stabilite con successo 8, 10, 11, 12. Tuttavia, anche questi test più avanzati non danno sufficiente attenzione alle barriere di penetrazione che i farmaci incontrano nelle lesioni polmonari non vascolarizzati, e di foci necrotici al sito di infezione. Infatti, Anche per la prima linea TB rifampicina farmaco, il dosaggio sub-ottimale è stata messa in discussione a causa di inadeguata nel tessuto vivo e liquido cerebrospinale (CSF) penetrazione 13, 14, 15, così come è diminuito l&#39;efficacia contro intracellulare Mtb 8, 9. Come tali, i nuovi modelli e le analisi che tengano conto di questi parametri durante il processo di sviluppo del cavo in anticipo sarebbe senza dubbio migliorare TB sforzi scoperta di nuovi farmaci. Per rispondere a questa esigenza, abbiamo recentemente istituito un poco costoso, rapido, e BSL 2-modello di infezione compatibile alternativo per Mtb droga prove di efficacia 16. Questo modello di infezione prodotta densamente Mtb all&#39;interno di grandi strutture aggregate macrofagi, che ricapitolava fisiologicamente rilevanti barriere di penetrazione cellulare e ha generato macrofagi diversi passaggi <em&gt; Mtb con uno stato fisiologico alterato simile latente Mtb. Mtb derivato da questo modello di infezione è stato combinato con il test resazurina microtitolazione (REMA) per valutare l&#39;efficacia della droga, che ha prodotto risultati coerenti con altri modelli di infezione intracellulare e correlato bene con la capacità riportato comuni farmaci TB di raggiungere alte concentrazioni di CSF relative alle concentrazioni sieriche 16. Qui si descrive in dettaglio la generazione di Mtb / macrofagi strutture aggregate per produrre macrofagi diversi passaggi Mtb adatto per i test di sensibilità ai farmaci utilizzando REMA. In particolare, si mostra come questo sistema di infezione potrebbe essere adattato in un formato a 96 pozzetti per la compatibilità con throughput screening di candidati farmaci anti-TB.

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>7H9</td>
			<td>BD Difco</td>
			<td>271310</td>
			<td>Follow manufacturer&#39;s recommendations</td>
		</tr>
		<tr>
			<td>Middlebrook OADC</td>
			<td>BD Biosciences</td>
			<td>212351</td>
			<td></td>
		</tr>
		<tr>
			<td>Tyloxapol</td>
			<td>Sigma</td>
			<td>T8761</td>
			<td>Prepare 20% stock solution in H2O; filter sterilize</td>
		</tr>
		<tr>
			<td>D-Pantothenic acid hemicalcium salt</td>
			<td>Sigma</td>
			<td>P5710</td>
			<td>Prepare 24 mg/ml&#160; stock solution in H2O; filter sterilize</td>
		</tr>
		<tr>
			<td>L-leucine</td>
			<td>MP Biomedicals</td>
			<td>194694</td>
			<td>Prepare 50 mg/ml&#160; stock solution in H2O; filter sterilize</td>
		</tr>
		<tr>
			<td>Hygromycin B</td>
			<td>EMD Millipore</td>
			<td>400051</td>
			<td>Prepare 200 mg/ml&#160; stock solution in H2O</td>
		</tr>
		<tr>
			<td>Nalgene Square PETG media bottle</td>
			<td>Thermo Fisher</td>
			<td>2019-0030</td>
			<td></td>
		</tr>
		<tr>
			<td>RPMI 1640 media</td>
			<td>Hyclone</td>
			<td>SH30027.01</td>
			<td></td>
		</tr>
		<tr>
			<td>Fetal Bovine Serum</td>
			<td>Atlanta Biologicals</td>
			<td>S12450H</td>
			<td></td>
		</tr>
		<tr>
			<td>L-glutamine</td>
			<td>Corning</td>
			<td>MT25005CI</td>
			<td></td>
		</tr>
		<tr>
			<td>HEPES</td>
			<td>Hyclone</td>
			<td>SH30237.01</td>
			<td></td>
		</tr>
		<tr>
			<td>Cytation 3 plate reader</td>
			<td>Biotek</td>
			<td></td>
			<td>Interchangable with any fluorescent plate reader and microscope</td>
		</tr>
		<tr>
			<td>Gen5 Software</td>
			<td>Biotek</td>
			<td></td>
			<td>Recording and analysis of rezasurin coversion</td>
		</tr>
		<tr>
			<td>Rifampicin&#160;</td>
			<td>Fisher Scientific</td>
			<td>BP2679250</td>
			<td>Prepare 10 mg/ml stock solution in H2O</td>
		</tr>
		<tr>
			<td>Moxifloxacin Hydrochloride</td>
			<td>Acros Organics</td>
			<td>457960010</td>
			<td>Prepare 10 mg/ml stock solution in H2O</td>
		</tr>
		<tr>
			<td>Resazurin Sodium Salt</td>
			<td>Sigma</td>
			<td>R7017</td>
			<td>Prepare 800 &#956;g/mL stock solution in H2O; filter sterilize</td>
		</tr>
		<tr>
			<td>Tween-80</td>
			<td>Fisher Scientific</td>
			<td>T164500</td>
			<td>Prepare 20% stock solution in H2O; filter sterilize</td>
		</tr>
	</tbody>
</table>

a high-throughput compatible assay to evaluate drug efficacy against macrophage passaged mycobacterium tuberculosis

The early drug development process for anti-tuberculosis drugs is hindered by the inefficient translation of compounds with in vitro activity to effectiveness in the clinical setting. This is likely due to a lack of consideration for the physiologically relevant cellular penetration barriers that exist in the infected host. We recently established an alternative infection model that generates large macrophage aggregate structures containing densely packed M. tuberculosis (Mtb) at its core, which was suitable for drug susceptibility testing. This infection model is inexpensive, rapid, and most importantly BSL-2 compatible. Here, we describe the experimental procedures to generate Mtb/macrophage aggregate structures that would produce macrophage-passaged Mtb for drug susceptibility testing. In particular, we demonstrate how this infection system could be directly adapted to the 96-well plate format showing throughput capability for the screening of compound libraries against Mtb. Overall, this assay is a valuable addition to the currently available Mtb drug discovery toolbox due to its simplicity, cost effectiveness, and scalability.

Per confermare la robustezza di adattare questo modello infezione per 96 pozzetti formato piatto, abbiamo qui esaminato la sensibilità ai farmaci di Mtb derivato dal nostro 96-ben adattata modello di infezione alla rifampicina (RIF) e moxifloxacina (Moxi) secondo il modello di data nella figura 1A. Abbiamo dimostrato che la generazione di Mtb / macrofagi strutture aggregate chiave per questa analisi può essere prodotto in maniera affidabile in un form...

Watch this Scientific Journal Video about A High-throughput Compatible Assay to Evaluate Drug Efficacy against Macrophage Passaged Mycobacterium tuberculosis at JoVE.com

A High-throughput Compatible Assay to Evaluate Drug Efficacy against Macrophage Passaged Mycobacterium tuberculosis

New models and assays that would improve the early drug development process for next-generation anti-tuberculosis drugs are highly desirable. Here, we describe a quick, inexpensive, and BSL-2 compatible assay to evaluate drug efficacy against Mycobacterium tuberculosis that can be easily adapted for high-throughput screening.

Un test compatibile high-throughput per valutare Drug efficacia contro macrofagi diversi passaggi<em&gt; Mycobacterium tuberculosis</em

The early drug development process for anti-tuberculosis drugs is hindered by the inefficient translation of compounds with in vitro activity to ...

Research

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Immunology and Infection

A High-throughput Compatible Assay to Evaluate Drug Efficacy against Macrophage Passaged Mycobacterium tuberculosis

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Zebrafish are becoming a valuable tool in the preclinical phase of drug discovery screenings as a whole animal model with high throughput screening ...

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Microdissection has been used for the examination of tissues at DNA, RNA, and protein levels for over a decade. Laser capture microscopy (LCM) is the most ...

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Described in this report is a qRT-PCR assay for the analysis of seventeen human IFN subtypes in a 384-well plate format that incorporates highly specific ...

A Robust Pneumonia Model in Immunocompetent Rodents to Evaluate Antibacterial Efficacy against S. pneumoniae, H. influenzae, K. pneumoniae, P. aeruginosa or A. baumannii

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Efficacy of candidate antibacterial treatments must be demonstrated in animal models of infection as part of the discovery and development process, ...

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Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), is a leading cause of morbidity and mortality worldwide. With the increased spread ...

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Un<em&gt; In vitro</em&gt; Test di rilascio di Caseum che prevede la penetrazione di farmaci nelle lesioni della tubercolosi

The eradication of tuberculosis disease requires drug regimens that can penetrate the multiple layers of complex pulmonary lesions. Drug distribution in ...

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