Antibiotic lethality dictates mycobacterial infection outcomes

Jovanovic, A.; Bright, F. K.; Sadeghi, A.; Wicki, B.; Muniz, S. E. C.; Toprak, S.; Sauteur, L.; Rodoni, A.; Wust, A.; Lupien, A.; Borrell, S.; Grogono, D. M.; Wheeler, N.; Dehio, P.; Nemeth, J.; Pargger, H.; Thomson, R.; Bell, S. C.; Gagneux, S.; Bryant, J. M.; Peng, T.; Diacon, A.; Floto, R. A.; Abanto, M.; Boeck, L.

doi:10.1101/2024.10.29.619904

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bioRxiv · 10.1101/2024.10.29.619904

Antibiotic lethality dictates mycobacterial infection outcomes

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Abstract

Antibiotic development and treatment focus on bacterial growth inhibition, often with limited success. Here, we introduce Antimicrobial Single-Cell Testing (ASCT), an advanced imaging strategy to assess bacterial killing in real-time. By tracking 140 million bacteria and generating over 20,000 in vitro time-kill curves, we can predict Mycobacterium tuberculosis treatment outcomes in mice and humans and link strain-specific survival (drug tolerance) in Mycobacterium abscessus to clinical responses. Using ASCT, we reveal drug tolerance as a distinct genetically encoded bacterial trait conserved across drugs with similar targets and, via genome-wide associations, uncover molecular mechanisms that govern bacterial killing. This study establishes the technical framework and in vivo validation for large-scale bacterial killing assessments to advance our understanding of bacterial survival, antibiotic development and clinical decision-making.

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Jovanovic, A., Bright, F. K., Sadeghi, A., Wicki, B., Muniz, S. E. C., Toprak, S., Sauteur, L., Rodoni, A., Wust, A., Lupien, A., Borrell, S., Grogono, D. M., Wheeler, N., Dehio, P., Nemeth, J., Pargger, H., Thomson, R., Bell, S. C., Gagneux, S., Bryant, J. M., Peng, T., Diacon, A., Floto, R. A., Abanto, M., Boeck, L.. 2024-10-29. Antibiotic lethality dictates mycobacterial infection outcomes. https://doi.org/10.1101/2024.10.29.619904

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