Investigating the molecular mechanisms underlying microbial persistence towards antibiotics

PhD project strategic theme: Biosciences for an integrated understanding of health

Bacteria can dodge antibiotics by two different types of mechanisms - resistance and persistence. Bacterial persistence is an epigenetic phenomenon in which a tiny fraction of the cell-population reversibly enter 'dormant' state and survive antibiotics. While our knowledge of the mechanisms behind resistance is quite sophisticated, the understanding of persistence is fairly limited. It is still unclear which molecular and genetic factors regulate the frequency of entry-exit and duration of this stochastic phenomenon, and how does the physiological signatures of this state relate to antibiotic tolerance. Due to the 'very rare' and 'transient' nature of this phenomenon, it has been very difficult to study this phenomenon using existing methods. The population-level methods employed in this research so far are also incapable of ensuring local uniformity of growth-conditions that is a strict requirement for studying these cellular outliers. In order to address these challenges, we have recently developed a platform for tracking >10^5 single bacterial-cells in parallel under precisely controlled growth-conditions (1). Using this platform, and a control-theoretic analysis of the relation between the molecular players and observed cellular kinetics, we will take a systems-level approach towards investigating the mechanisms of the formation and antibiotic tolerance of persister cells.