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Published on: March 2, 2020
Fluorescent probes for investigating peptidoglycan biosynthesis in mycobacteria
1Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, United States.
Abstract:
Tuberculosis killed 1.5 million people in 2018. Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, is the most deadly infectious bacteria in the world. A strength of mycobacterial pathogens - their formidable cell wall - could also be one of their greatest molecular vulnerabilities. As in other bacteria, peptidoglycan (PG) maintenance and integrity is essential to mycobacterial survival. But Mtb PG is unique, and a better understanding of its biosynthetic machinery could lead to new drugs or more effective treatment regimens. Such investigations are being accelerated by the application of fluorescent probes, including those based on vancomycin, β-lactams, PG stem mimics, d-amino acids, and reactive glycans. This review will describe how fluorescent probes are being used to uncover new information on the regulation and drug susceptibility of two classes of enzymes that fortify the Mtb PG: the penicillin-binding proteins and the L,D-transpeptidases.
Insights
Fluorescent probes reveal vulnerabilities in Mycobacterium tuberculosis (Mtb) cell wall synthesis. Understanding these mechanisms can lead to new tuberculosis treatments targeting essential enzymes.
Area of Science:
- Microbiology
- Biochemistry
- Drug Discovery
Background:
- Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a leading infectious cause of death globally.
- The unique cell wall of Mtb, particularly its peptidoglycan (PG) layer, is crucial for survival but also presents a potential therapeutic target.
- Existing knowledge of Mtb PG biosynthesis is limited, hindering the development of novel anti-TB drugs.
Purpose of the Study:
- To review the application of fluorescent probes in studying Mtb PG biosynthesis.
- To highlight how these probes aid in understanding the function and drug susceptibility of key enzymes involved in PG maintenance.
- To explore the potential for developing new therapeutic strategies targeting Mtb PG synthesis.
Main Methods:
- Utilizing fluorescent probes, including vancomycin, β-lactams, PG stem mimics, d-amino acids, and reactive glycans.
- Investigating the regulation and drug susceptibility of penicillin-binding proteins (PBPs) and L,D-transpeptidases (LDTs) in Mtb.
- Analyzing the role of these enzymes in maintaining PG integrity.
Main Results:
- Fluorescent probes provide dynamic insights into Mtb PG synthesis and remodeling.
- These tools have uncovered new information on the activity and inhibition of PBPs and LDTs.
- The unique PG structure of Mtb offers specific targets for novel antimicrobial agents.
Conclusions:
- Fluorescent probes are powerful tools for dissecting Mtb PG biosynthesis.
- Targeting PBPs and LDTs involved in PG synthesis presents a promising avenue for new anti-TB drug development.
- Further research using these probes could accelerate the discovery of more effective tuberculosis treatments.
