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Bacterial resistance has become a major threat to global public health, and traditional antibiotic research has reached a bottleneck. Chiral peptidoglycan mimics, as a new type of antibacterial molecule with a novel structure, precisely target the bacterial cell wall synthesis pathway, do not rely on traditional targets, and show strong bactericidal activity against multi-drug resistant bacteria, bringing new solutions to the fields of nanomedicine and anti-infection. The related research results were published in "Nature Communications" under the title "Chiral peptidoglycan mimics target bacterial wall biosynthesis for pathogen intervention".
Key analysis
I. Research background: New target breakthrough under the crisis of antibiotic resistance
The synthesis of bacterial cell wall peptidoglycan is a necessary pathway for bacterial survival, and there is no homologous target in the human body, which ensures high safety.
Existing antibiotics (such as β-lactams, glycopeptides) have been used for a long time, leading to widespread antibiotic resistance.
The chiral structure is the key to biomolecular recognition, and chiral peptidoglycan mimics can achieve high selectivity targeting.
II. Core innovation: Chiral-driven precise antibacterial mechanism
1. Molecular design: From natural framework to optimized simulation
The research team used the bacterial peptidoglycan precursor as the core framework and conducted systematic structural optimization:
Retain the core framework of the natural sugar-peptide unit to ensure the basic recognition ability with the target enzyme;
Introduce controllable chiral centers to optimize the binding mode of the molecule with transglycosylase/transpeptidase;
Modify hydrophobic groups and charge distribution to improve the penetration efficiency and intracellular stability of the bacterial membrane.
Through high-throughput screening and molecular dynamics simulation, finally three optimal chiral mimics were obtained, and their binding affinity to the target enzyme was more than 100 times higher than the natural substrate.
2. Mechanism of action: Precise blockade of cell wall synthesis with "double blow"
In vitro enzymatic experiments and structural biology studies revealed that chiral peptidoglycan mimics blocked bacterial cell wall synthesis through dual mechanisms:
Competitive inhibition of transglycosylase: Simulate the natural sugar chain precursor, occupy the active center of the enzyme, and prevent the extension of the sugar chain;
Non-competitive interference of transpeptidase: Bind to the allosteric site of the transpeptidase, disrupt the peptide chain cross-linking reaction, and cause fragmentation of the cell wall structure.
This dual action mode makes it difficult for bacteria to develop resistance through single-point mutations, reducing the risk of resistance at the root.
3. Antibacterial activity: Broad-spectrum and potent, directly targeting "super bacteria"
In vitro antibacterial spectrum
For Gram-positive bacteria (MRSA, VRE, Streptococcus pneumoniae): MIC as low as 0.016–0.125 μg/mL, superior to clinical first-line drugs such as vancomycin and linezolid;
For Gram-negative bacteria (CRE, Pseudomonas aeruginosa): MIC is 0.5–2 μg/mL, breaking through the bottleneck that traditional glycopeptides cannot penetrate the outer membrane;
For mycobacteria (Mycobacterium tuberculosis): Also shows significant inhibitory activity, providing new ideas for the development of anti-tuberculosis drugs.
In vivo anti-infection effect
In mouse sepsis models and skin infection models:
The bacterial load in the chronic simulation treatment group was reduced by 3–5 orders of magnitude compared to the control group;
Significantly improved tissue inflammation damage, survival rate increased to over 80% (compared to 20% in the control group);
When used in combination with clinical antibiotics, it shows a synergistic bactericidal effect, further reducing the dosage and side effects of medication.
4. Resistance and safety: Key guarantee for clinical translation
Resistance induction experiment: After continuous passage for 30 generations, no obvious resistance mutations were observed, while the control antibiotic group developed resistant strains within 10 generations;
Cell toxicity: The IC₅₀ of the IC₅₀ for human red blood cells, epithelial cells, and immune cells was > 100 μg/mL, with a treatment index (TI) > 1000; Metabolism in the body: Mainly excreted through the kidneys. There is no significant accumulation in organs. No abnormal changes were observed in liver and kidney function indicators.
（doi）: https://www.nature.com/articles/s41467-026-69967-z
