Peptidoglycan Biosynthesis Inhibitors in Bacterial Systems

Bacterial peptidoglycan is a unique heteropolymer that confers shape and mechanical strength to the cell envelope. Its assembly begins in the cytoplasm with the formation of UDP-N-acetylmuramoyl-pentapeptide through the concerted action of Mur enzymes (MurA–MurF), followed by membrane translocation and polymerisation into a cross-linked sacculus. Inhibitors of this pathway range from classical β-lactams and glycopeptides, which target late-stage transpeptidases or lipid II intermediates, to novel agents directed at cytoplasmic Mur ligases and transferases. Advances in high-resolution crystallography, solution scattering and enzymology have uncovered dynamic conformational states of key Mur proteins, guiding structure-based drug design. Parallel developments in high-throughput and multi-enzyme screening assays now enable simultaneous interrogation of several Mur targets, thus accelerating the discovery of broad-spectrum and species-selective leads. Addressing emerging resistance demands chemical diversity, multi-target engagement and exploitation of bacterial-specific active sites, offering a pathway to next-generation antibacterials with reduced cross-resistance potential.

Research from Nature Portfolio

Recent studies have introduced a one-pot assay reconstructing the entire Mycobacterium tuberculosis MurA–MurF pathway in vitro, eliminating the need for nucleotide intermediates and enabling high-throughput screening against multiple ligases simultaneously. This platform has been biochemically characterised and applied to validate known inhibitors such as D-Cycloserine alongside novel furan-based benzene derivatives, demonstrating inhibition of both MurE and MurF activities and underscoring the value of multiplexed pathway assays in accelerating early-stage inhibitor discovery.

Peptidoglycan Biosynthesis Inhibitors in Bacterial Systems publication trend

The graph below shows the total number of articles in peptidoglycan biosynthesis inhibitors in bacterial systems across all publications each year (not limited to Nature Index journals).

Technical terms

Peptidoglycan: A mesh-like polymer of glycan strands cross-linked by short peptides, essential for bacterial cell-wall integrity.

Mur enzymes (MurA–MurF): A series of cytoplasmic enzymes that catalyse successive additions of amino acids to UDP-MurNAc, forming the pentapeptide precursor of peptidoglycan.

UDP-N-acetylmuramoyl-pentapeptide: The nucleotide-linked peptidoglycan precursor assembled by Mur ligases before membrane translocation.

Lipid II: A membrane-bound disaccharide-pentapeptide that serves as the immediate substrate for cell-wall polymerases and transpeptidases.

High-throughput screening: Automated evaluation of large compound libraries against one or more enzymatic targets to identify active inhibitors.

References

1. Anti-Tuberculosis Mur Inhibitors: Structural Insights and the Way Ahead for Development of Novel Agents. Pharmaceuticals (2023).
2. Antibiotics and Antibiotic Resistance—Mur Ligases as an Antibacterial Target. Molecules (2023).
3. Development of a one-pot assay for screening and identification of Mur pathway inhibitors in Mycobacterium tuberculosis. Scientific Reports (2016).
4. Evaluation of the published kinase inhibitor set to identify multiple inhibitors of bacterial ATP-dependent mur ligases. Journal of Enzyme Inhibition and Medicinal Chemistry (2019).
5. Design and Synthesis of Various 5′-Deoxy-5′-(4-Substituted-1,2,3-Triazol-1-yl)-Uridine Analogues as Inhibitors of Mycobacterium tuberculosis Mur Ligases. Molecules (2020).