High-throughput screening of small molecules targeting Mycobacterium tuberculosis in human iPSC macrophages Articles uri icon

authors

  • MENDOZA LOSANA, ALFONSO
  • ARENAZ, MARIA PILAR
  • ASHBY, CHARLOTTE
  • BLANCO, DELIA
  • D'ORIA, EMILIANA
  • GARUTI, HELENA
  • GÓMEZ, VANESA
  • GONZÁLEZ DEL RÍO, RUBÉN
  • MARTÍNEZ HOYOS, MARÍA
  • MEILER, EUGENIA
  • MOHAMET, LISA
  • PADRON BARTHE, LAURA
  • PEREZ, ESTHER
  • PEREZ, LAURA
  • REMUIÑÁN, MODESTO J.
  • RODRIGUEZ MIQUEL, BEATRIZ
  • SEGURA CARRO, DELFINA
  • VIERA MORILLA, SARA

publication date

  • May 2025

start page

  • 1

end page

  • 14

International Standard Serial Number (ISSN)

  • 0066-4804

Electronic International Standard Serial Number (EISSN)

  • 1098-6596

abstract

  • New treatments are still necessary to eradicate tuberculosis disease. Macrophages derived from human induced pluripotent stem cells (hiPSC-Macs) offera physiological niche to identify potential new drugs in the context of Mycobacterium tuberculosis (Mtb) infection. Here, we describe the scale-up of hiPSC-Macs production in 5-stack chambers for high-throughput drug screening against Mtb. A rate of approximately 100 million hiPSC-Macs was generated with optimal quality for a period of up to 12 weeks. Moreover, the infection model was optimized using a luminescence-based Mtb reporter strain. The assay showed enough sensitivity to identify compounds that could target host-pathogen interactions during Mtb infection. We interrogated a library of 200,000 compounds in Mtb-infected hiPSC-Macs with a Z-score above 0.3 in all plates analyzed. After secondary assays, 223 qualifiedhits were selected for further progression.

subjects

  • Biology and Biomedicine
  • Medicine

keywords

  • drug screening; host-pathogen interactions; human induced pluripotent stem cells; macrophages; tuberculosis.