Investigating the molecular mechanisms underlying microbial persistence towards antibiotics

细菌可以通过两种不同的机制——耐药性和持久性来躲避抗生素。细菌持久性是一种表观遗传现象，其中一小部分细胞群可逆地进入“休眠”状态，并在抗生素中存活下来。虽然我们对抗性背后机制的了解相当复杂，但对持久性的理解却相当有限。目前尚不清楚是哪些分子和遗传因素调节了这种随机现象的进出频率和持续时间，以及这种状态的生理特征与抗生素耐受性之间的关系。由于这种现象“非常罕见”和“短暂”的性质，使用现有方法研究这种现象非常困难。到目前为止，本研究中采用的群体水平方法也无法确保生长条件的局部均匀性，而这是研究这些细胞异常值的严格要求。为了应对这些挑战，我们最近开发了一个平台，用于在精确控制的生长条件下并行跟踪bb10 ^5个单个细菌细胞(1)。利用这个平台，以及对分子参与者和观察到的细胞动力学之间关系的控制理论分析，我们将采取系统级的方法来研究持久性细胞的形成和抗生素耐受性的机制。

PhD project strategic theme: Biosciences for an integrated understanding of healthBacteria 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.