A bioengineered three-dimensional cell culture platform integrated with microfluidics to address antimicrobial resistance in tuberculosis
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Antimicrobial resistance presents one of the most significant threats to human health, with the emergence of totally drug-resistant organisms. We have combined bioengineering, genetically modified bacteria, longitudinal readouts, and fluidics to develop a transformative platform to address the drug development bottleneck, utilizing Mycobacterium tuberculosis as the model organism. We generated microspheres incorporating virulent reporter bacilli, primary human cells, and an extracellular matrix by using bioelectrospray methodology. Granulomas form within the three-dimensional matrix, and mycobacterial stress genes are upregulated. Pyrazinamide, a vital first-line antibiotic for treating human tuberculosis, kills M. tuberculosis in a three-dimensional culture but not in a standard two-dimensional culture or Middlebrook 7H9 broth, demonstrating that antibiotic sensitivity within microspheres reflects conditions in patients. We then performed pharmacokinetic modeling by combining the microsphere system with a microfluidic plate and demonstrated that we can model the effect of dynamic antibiotic concentrations on mycobacterial killing. The microsphere system is highly tractable, permitting variation of cell content, the extracellular matrix, sphere size, the infectious dose, and the surrounding medium with the potential to address a wide array of human infections and the threat of antimicrobial resistance.
Date Issued
2017-02-07
Date Acceptance
2017-01-12
Citation
MBIO, 2017, 8 (1)
ISSN
2150-7511
Publisher
American Society for Microbiology
Journal / Book Title
MBIO
Volume
8
Issue
1
Copyright Statement
© 2017 Bielecka et al. This is an
open-access article distributed under the terms
of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/).
open-access article distributed under the terms
of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/).
Sponsor
Medical Research Council (MRC)
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000395835000004&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Grant Number
515330101
Subjects
Science & Technology
Life Sciences & Biomedicine
Microbiology
MYCOBACTERIUM-TUBERCULOSIS
ANTIBIOTIC-RESISTANCE
EXTRACELLULAR-MATRIX
IN-VITRO
ANTITUBERCULOSIS DRUGS
HOST
PYRAZINAMIDE
EXPRESSION
EVOLUTION
PATHOGEN
0605 Microbiology
Publication Status
Published
Article Number
ARTN e02073-16