The success of Mycobacterium tuberculosis (Mtb), the causative agent of Tuberculosis (TB), is related to its ability to enter a dormant, or inactive, state within a host. In this state, Mtb is virtually indetectable, tends to be drug-tolerant, and evades the human immune response. When infected with dormant Mtb, the host is entirely asymptomatic; however, dormant Mtb can be reactivated upon which the host would begin to experience symptoms and could become contagious. Even so, current therapeutic treatments tend to target the active growth state of Mtb and do not prevent its reactivation from the dormant state. The behavior of Mtb highlights the potential for alternative methods of treatment that prevent dormant Mtb from reactivating. Serine hydrolases are a class of enzymes essential to maintenance of a dormant infection, as their cleavage of triacylglycerols (TAGs) provide a major energy source for dormant Mtb. This research examined the role of serine hydrolases in both the survival and reactivation of dormant Mtb. The study first investigated whether Mycobacterium smegmatis (M. smeg) can be used as a model organism for Mtb. A growth system with M. smeg was developed that mimicked the TAG concentrations and relative activities of serine hydrolases previously observed in Mtb for both dormant and activated cultures. By using TLC for analysis, the growth system showed an increase in TAG concentrations with increasing amounts of supplied carbon, modeled by variations in glycerol concentration (0%, 1%, 2% and 5%). It also revealed a decrease in TAG concentrations with increasing activation time, which was modeled with variations in time of nitrogen exposure (0 hr., 3 hr. or 6 hr.) after being grown in an environment with limited nitrogen. These results mimicked both the derivation of TAGs by Mtb upon infection and their cleavage upon reactivation. Furthermore, by using variable ester substrates designed to mimic TAG and other nutritional lipids, specific serine hydrolases were identified with changes in activity across active and dormant growth conditions as future targets for TB treatment.

Shifted activity of serine hydrolases in Mycobacterium smegmatis during the dormant to active transition

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ACS Fall 2022

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