DPA: A Promising Inhibitor of NDM-1 Metallo-β-Lactamase
2,6-Dipicolinic acid (DPA) effectively inhibits NDM-1, a zinc-dependent enzyme that confers antibiotic resistance.
This presentation explores DPA's mechanisms, efficacy, and potential as a clinical solution to combat antimicrobial resistance.

by FNU Ashish

Structure and Active Site Interaction

Zinc Chelation
Strong binding to zinc ions in active site
Tridentate Binding
Two carboxyl groups plus pyridine nitrogen coordinate metals
Active Site Disruption
Prevents substrate access and catalytic function
Zinc Chelation Mechanism
Zinc Binding
DPA forms coordination complex with Zn1 and Zn2 ions
Ion Displacement
DPA can remove or reposition critical zinc ions
Catalytic Shutdown
Loss of Zn2 severely impairs enzymatic function
Antibiotic Protection
Prevents β-lactam hydrolysis by NDM-1
Competitive Inhibition

Substrate Mimicry
DPA mimics β-lactam antibiotics at binding site

Key Residue Interactions
Binds to Asp124, His250, and active site loops

Stable Complex
Forms thermodynamically favorable Zn-DPA complex

Site Obstruction
Physically blocks antibiotic access to catalytic center
Structural Effects on NDM-1
Loop Flexibility Disruption
DPA binding rigidifies flexible L3 and L10 loops critical for enzyme function.
This restricts substrate recognition and catalytic positioning.
Electrostatic Interference
Negative charges from carboxyl groups repel Asp124.
This creates active site distortions that misalign catalytic machinery.
Hydrophobic Pocket Interactions
DPA derivatives engage with hydrophobic wall residues like Trp93.
These interactions enhance binding affinity and inhibitory potency.
Antibiotic Synergy
Mechanism
DPA has no direct antibacterial activity.
It preserves β-lactam antibiotics by preventing their degradation.
This restores effectiveness against resistant bacteria.
Synergy demonstrated by increased zones of inhibition when DPA is combined with carbapenems.
Effectiveness
Reduces minimum inhibitory concentration (MIC) by 8-16 fold.
Works against multiple metallo-β-lactamase types including VIM-2 and IMP-1.
Broad-spectrum activity across various resistant bacterial strains.
Optimized DPA Derivatives
10-50μM
Base DPA IC50
Standard inhibition concentration of unmodified DPA
80nM
Enhanced Derivatives
Lowest IC50 achieved with optimized variants
625×
Potency Increase
Maximum improvement factor from base compound
The 4-(3-aminophenyl) derivative provides superior binding by adding hydrophobic interactions with Trp93 and Phe70 residues.
Clinical Development Challenges

Toxicity Screening
Ensuring selectivity for bacterial vs. human metalloproteins
Formulation Development
Addressing solubility and bioavailability concerns
Resistance Profiling
Testing against NDM variants (NDM-4, NDM-5)
Despite these challenges, DPA provides a promising scaffold for developing clinically viable metallo-β-lactamase inhibitors to combat antimicrobial resistance.