Mycobacterial Adaptation and Enzymatic Responses in Host Environments

Mycobacteria confront a range of challenges upon entering host tissues, including nutrient limitation, oxidative stress and immune surveillance. Successful pathogens remodel their complex cell envelope, deploy specialised enzymes to scavenge host lipids and adjust central metabolism to persist in both active and dormant states. Key adaptations involve regulated expression of lipolytic enzymes and serine hydrolases that hydrolyse host-derived triacylglycerols into fatty acids for energy and cell-wall biosynthesis. Concurrently, efflux pumps and modifications of mycolic acids restrict drug penetration and modulate host immune recognition. In nutrient-starved or hypoxic microenvironments, a shift towards non-replicative persistence is underpinned by induction of hormone-sensitive lipases and carboxylesterases that catalyse lipid turnover, sustaining basal metabolic flux. Cross-talk between bacterial and host signalling pathways further shapes cytokine responses, allowing intracellular survival within macrophages. Collectively, these enzymatic strategies orchestrate the transition between latency and reactivation, underpinning global disease persistence and informing new therapeutic approaches targeting metabolic and cell-wall enzymes.

Research from Nature Portfolio

A novel class of cyclophostin and cyclipostin analogues has been shown to exert potent antimycobacterial activity by covalently modifying multiple serine and cysteine enzymes involved in lipid metabolism and cell-wall assembly. These multi-target inhibitors impair the antigen 85 complex, blocking trehalose dimycolate synthesis and mycolylation of arabinogalactan, thus arresting bacterial growth both extracellularly and within macrophages. High-resolution structural analyses of inhibitor–enzyme complexes reveal precise interactions in the catalytic pocket, guiding rational optimisation of scaffolds with enhanced specificity and potency against persistent mycobacterial populations.

Mycobacterial Adaptation and Enzymatic Responses in Host Environments publication trend

The graph below shows the total number of articles in mycobacterial adaptation and enzymatic responses in host environments across all publications each year (not limited to Nature Index journals).

Technical terms

Lipolytic enzymes: Enzymes that hydrolyse lipid substrates to release fatty acids and glycerol.
Serine hydrolases: A broad superfamily of enzymes using an active serine residue to catalyse hydrolysis of ester and amide bonds.
Carboxylesterases: Enzymes of the α/β-hydrolase fold that cleave ester bonds in cell-envelope lipids.
Catalytic triad: A set of three amino acids—usually serine, histidine and aspartate—that cooperate to mediate enzyme catalysis.
Latency (dormancy): A non-replicating state of mycobacteria within host tissues characterised by metabolic downregulation and drug tolerance.

References

1. Roles of Lipolytic enzymes in Mycobacterium tuberculosis pathogenesis. Frontiers in Microbiology (2024).
2. Shifting Mycobacterial Serine Hydrolase Activity Visualized Using Multi-Layer In-Gel Activity Assays. Molecules (2024).
3. Sequence and Structural Motifs Controlling the Broad Substrate Specificity of the Mycobacterial Hormone-Sensitive Lipase LipN. ACS Omega (2023).
4. A Novel Lipase Belonging to the Hormone-sensitive Lipase Family Induced under Starvation to Utilize Stored Triacylglycerol in Mycobacterium tuberculosis *. Journal of Biological Chemistry (2005).
5. Mycobacterium tuberculosis Rv3402c Enhances Mycobacterial Survival within Macrophages and Modulates the Host Pro-Inflammatory Cytokines Production via NF-Kappa B/ERK/p38 Signaling. PLOS ONE (2014).
6. Cyclipostins and Cyclophostin analogs as promising compounds in the fight against tuberculosis. Scientific Reports (2017).