Abstract
BackgroundProteins that are involved in regulation of cell division and cell cycle progression remain undefined in Mycobacterium tuberculosis. In addition, there is a growing appreciation that regulation of cell replication at the point of division is important in establishing a non-replicating persistent state. Accordingly, the objective of this study was to use a systematic approach consisting of consensus-modeling bioinformatics, ultrastructural analysis, and transcriptional mapping to identify septum regulatory proteins that participate in adaptive metabolic responses in M. tuberculosis.ResultsSeptum site determining protein (Ssd), encoded by rv3660c was discovered to be an ortholog of septum site regulating proteins in actinobacteria by bioinformatics analysis. Increased expression of ssd in M. smegmatis and M. tuberculosis inhibited septum formation resulting in elongated cells devoid of septa. Transcriptional mapping in M. tuberculosis showed that increased ssd expression elicited a unique response including the dormancy regulon and alternative sigma factors that are thought to play a role in adaptive metabolism. Disruption of rv3660c by transposon insertion negated the unique transcriptional response and led to a reduced bacterial length.ConclusionsThis study establishes the first connection between a septum regulatory protein and induction of alternative metabolism consisting of alternative sigma factors and the dormancy regulon that is associated with establishing a non-replicating persistent intracellular lifestyle. The identification of a regulatory component involved in cell cycle regulation linked to the dormancy response, whether directly or indirectly, provides a foundation for additional studies and furthers our understanding of the complex mechanisms involved in establishing a non-replicating state and resumption of growth.
Highlights
Proteins that are involved in regulation of cell division and cell cycle progression remain undefined in Mycobacterium tuberculosis
Proteins that regulate septum formation as part of growth arrest and altered metabolic responses associated with the persistent state remain undefined in M. tuberculosis
In M. tuberculosis inhibition of FtsZ polymerization and cell division occurs in response to stress conditions, which include environmental changes that occur during pathogenesis and drug treatment
Summary
Proteins that are involved in regulation of cell division and cell cycle progression remain undefined in Mycobacterium tuberculosis. The unremitting global burden is attributed, in part, to the ability of M. tuberculosis to establish and maintain a non-replicating formation as part of growth arrest and altered metabolic responses associated with the persistent state remain undefined in M. tuberculosis. It is important to identify regulatory elements involved in septum formation and the cell cycle in context of adaptive metabolism and to the development of a non-replicating persistent state. Inhibition of septum formation through the regulation of FtsZ polymerization represents a common mechanism that is conserved among bacteria, including M. tuberculosis, to control cell division and cell cycle activity in response to various conditions including stress [8]
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