Structural Insights into the Staphylococcus aureus DltC-Mediated D-Alanine Transfer
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Updated: Jan 29, 2026
Methodology for the Study of Horizontal Gene Transfer in Staphylococcus aureus
Published on: March 10, 2017
Hanul Jeon1, Hyebin Lee2,3, Chiman Song2,4
1College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.
Abstract:
Staphylococcus aureus (S. aureus) is a major Gram-positive pathogen, and treatment of S. aureus infections is often challenging due to widespread antibiotic resistance. In Gram-positive bacteria such as S. aureus, D-alanylation of teichoic acids (TA) reduces the net negative charge of the cell envelope and contributes to resistance to diverse antibiotics, particularly cationic antimicrobial peptides. D-alanylation is mediated by the dltABCD operon, which encodes four proteins (DltA, DltB, DltC, and DltD), all of which is essential for the multistep transfer of D-alanine to teichoic acids. Here, we present the first crystal structure of the S. aureus D-alanyl carrier protein DltC and analyze its interaction with DltA using AlphaFold3 and all-atom molecular dynamics simulations. We further show that single substitutions of SaDltA-SaDltC interface residues abolish SaDltC mediated enhancement of SaDltA catalysis. Together, these findings define a catalytically critical S. aureus DltA-DltC interface and provide a structural insight for targeting the D-alanylation pathway as a potential anti-Staphylococcus strategy.
Insights
Staphylococcus aureus D-alanylation, essential for antibiotic resistance, involves DltC and DltA proteins. We determined the DltC structure and identified a critical interface, offering a new target to combat S. aureus infections.
Area of Science:
- Microbiology
- Structural Biology
- Biochemistry
Background:
- Staphylococcus aureus is a significant pathogen causing challenging infections due to antibiotic resistance.
- D-alanylation of teichoic acids (TA) in S. aureus reduces cell envelope negative charge, enhancing resistance to antibiotics, especially cationic antimicrobial peptides.
- The dltABCD operon encodes essential proteins for D-alanine transfer to TA.
Purpose of the Study:
- To determine the crystal structure of Staphylococcus aureus DltC, a D-alanyl carrier protein.
- To analyze the interaction between S. aureus DltC and DltA using computational methods.
- To identify critical interface residues for DltA-DltC interaction and catalytic activity.
Main Methods:
- X-ray crystallography to determine the structure of S. aureus DltC.
- AlphaFold3 and all-atom molecular dynamics simulations to analyze protein-protein interactions.
- Site-directed mutagenesis to investigate the functional impact of interface residue substitutions.
Main Results:
- The first crystal structure of S. aureus DltC was determined.
- Computational analysis revealed key interactions between S. aureus DltA and DltC.
- Mutations at the DltA-DltC interface abolished DltC-mediated enhancement of DltA catalysis, highlighting its functional importance.
Conclusions:
- A catalytically critical interface between S. aureus DltA and DltC was defined.
- Structural insights into the D-alanylation pathway provide a basis for developing novel anti-Staphylococcus strategies.
- Targeting the D-alanylation pathway presents a potential avenue to overcome S. aureus antibiotic resistance.
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