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bioRxiv · 10.1101/2025.02.12.637810

Comparative Modeling of Antibiotic Resistance, Tolerance, and Persistence in Mycobacterium tuberculosis and Staphylococcus aureus

Piranfar, V.
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Abstract

Antibiotic resistance, tolerance, and persistence represent key bacterial survival strategies that impact treatment outcomes and global health. While Staphylococcus aureus is a rapidly growing pathogen associated with acute infections, Mycobacterium tuberculosis exhibits slow growth and chronic persistence, necessitating prolonged antibiotic regimens. In this study, we developed a state-structured pharmacodynamic model in which replicating and dormant subpopulations each carry their own concentration-response, so that the three strategies separate onto distinct measurable axes: resistance shifts the minimum inhibitory concentration, tolerance multiplies the minimum duration for killing, and persistence lifts the deep killing endpoint alone. Using global variance-based sensitivity analysis and profile likelihood, we identified which parameter governs the length of therapy and which parameters can be estimated at all from time-kill data. Our findings show that in the slow-growing organism 87% of the first-order variance in time to sterilisation is carried by the rate at which dormant cells resume replication, rather than by the rate at which dormant cells are killed, placing resuscitation at the centre of regimen shortening and identifying a class of intervention worth measuring. This version supersedes version 1, whose closed-form biphasic killing law is discontinuous and whose quantitative results are withdrawn and corrected here; the work is a modelling and methods contribution, contains no experimental data, and its parameter values are illustrative rather than measured.

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Piranfar, V.. 2025-02-14. Comparative Modeling of Antibiotic Resistance, Tolerance, and Persistence in Mycobacterium tuberculosis and Staphylococcus aureus. https://doi.org/10.1101/2025.02.12.637810

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