Scientific Reports (Apr 2022)

A combination screening to identify enhancers of para-aminosalicylic acid against Mycobacterium tuberculosis

  • Jinyeong Heo,
  • Dahae Koh,
  • Minjeong Woo,
  • Doyoon Kwon,
  • Virgínia Carla de Almeida Falcão,
  • Connor Wood,
  • Honggun Lee,
  • Kideok Kim,
  • Inhee Choi,
  • Jichan Jang,
  • Priscille Brodin,
  • David Shum,
  • Vincent Delorme

DOI
https://doi.org/10.1038/s41598-022-08209-w
Journal volume & issue
Vol. 12, no. 1
pp. 1 – 14

Abstract

Read online

Abstract Para-aminosalicylic acid (PAS) is an antibiotic that was largely used for the multi-therapy of tuberculosis in the twentieth century. To try to overcome the inconvenience of its low efficacy and poor tolerance, we searched for novel chemical entities able to synergize with PAS using a combination screening against growing axenic Mycobacterium tuberculosis. The screening was performed at a sub-inhibitory concentration of PAS on a library of about 100,000 small molecules. Selected hit compounds were analyzed by dose–response and further probed with an intracellular macrophage assay. Scaffolds with potential additive effect with PAS are reported, opening interesting prospects for mechanism of action studies. We also report here evidence of a yet unknown bio-activation mechanism, involving activation of pyrido[1,2-a]pyrimidin-4-one (PP) derivatives through the Rv3087 protein.