REVIEW: Biochemistry of Reactivation of Dormant Mycobacteria

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Margarita O. Shleeva^1,a*, Galina R. Demina¹, Arseny S. Kaprelyants¹

¹Federal Research Centre “Fundamentals of Biotechnology”, A. N. Bach Institute of Biochemistry, Russian Academy of Sciences, 119071 Moscow, Russia

^* To whom correspondence should be addressed.

Received: May 16, 2024; Revised: June 15, 2024; Accepted: August 23, 2024

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An important aspect of medical microbiology is identification of the causes and mechanisms of reactivation (resuscitation) of dormant non-sporulating bacteria. In particular, dormant Mycobacterium tuberculosis (Mtb) can cause latent tuberculosis (TB), which could be reactivated in the human organism to the active form of the disease. Analysis of experimental data suggested that reactivation of mycobacteria and reversion of the growth processes include several stages. The initial stage is associated with breakdown of the storage substances like trehalose upon the action of trehalase and with peptidoglycan hydrolysis. Demethylation of tetramethyl porphyrins accumulated in hydrophobic sites (membranes) of the dormant cell also occur in this stage. Metabolic reactivation, starting with cAMP synthesis and subsequent activation of metabolic reactions and biosynthetic processes take place at the stage two as has been shown in the omics studies. Mechanisms of cell reactivation by exogenous free fatty acids via activation of adenylate cyclase and cAMP production have been also suggested. Onset of the cell division is a key benchmark of the third and final stage. Hydrolysis of peptidoglycan as a result of enzymatic action of peptidoglycan hydrolases of the Rpf family is an important process in reactivation of the dormant mycobacteria. Two possible mechanisms for participation of Rpf proteins in reactivation of the dormant bacteria are discussed. On the one hand, muropeptides could be formed as products of peptidoglycan hydrolysis, which could interact with appropriate receptors in bacterial cells transducing activating signal via the PknB phosphotransferase. On the other hand, Rpf protein could presumably change structure of the cell wall, making it more permeable to nutrients and substrates. Both hypotheses were examined in this review. Upon reactivation, independent enzymatic reactions resume their functioning from the beginning of reactivation. Such activation of the entire metabolism occurs rather stochastically, which concludes in combining all biochemical processes in one. This review presents current knowledge regarding biochemical mechanisms of the dormant mycobacteria reactivation, which is important for both fundamental and medical microbiology.

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KEY WORDS: Mycobacterium tuberculosis, Mycobacterium smegmatis, reactivation, “non-cultivability”, dormant mycobacteria

DOI: 10.1134/S0006297924603757

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