MILD NUTRIENT STARVATION TRIGGERS THE DEVELOPMENT OF A SMALL-CELL SURVIVAL MORPHOTYPE IN MYCOBACTERIA

Abstract

Mycobacteria, generally believed to be non-differentiating, are well known to survive shock starvation in saline for extended periods of time in a non-replicating state without any apparent morphological changes. Here we uncover that mycobacteria actually harbor a novel, starvation-induced differentiation program in which first septated multi-nucleoided cells are generated. Under zero-nutrient conditions, bacteria terminate development at this stage as large resting cells (LARCs). In the presence of traces of nutrient, these multi-nucleoided cells continue differentiation to mono-nucleoided small resting cells (SMRCs). Both SMRCs and LARCs exhibited extreme antibiotic tolerance. SMRCs showed increased long-term starvation survival, which was associated with the presence of lipid inclusion bodies. Interestingly, the stringent response regulator RelA appeared to play the role of cellular differentiation other than a starvation survival factor in this process.