The New Delhi Metallo-β-lactamase-1 Covalent Inhibitors Derived from Cephalexin Effectively Reverse Meropenem...

Area of Science:

• Medicinal Chemistry
• Antimicrobial Resistance
• Enzyme Inhibitors

Background:

• New Delhi metallo-β-lactamase-1 (NDM-1) confers resistance to critical β-lactam antibiotics, including carbapenems.
• The rise of NDM-1-producing bacteria represents a significant global health threat, necessitating novel therapeutic strategies.
• Effective inhibitors are urgently required to combat NDM-1-mediated antibiotic resistance.

Purpose of the Study:

• To design and synthesize novel covalent inhibitors targeting the NDM-1 enzyme.
• To evaluate the inhibitory activity and in vivo efficacy of these novel compounds.
• To elucidate the mechanism of action for potent NDM-1 inhibitors.

Main Methods:

• Design and synthesis of cephalexin-based compounds incorporating a selenazolone warhead.
• Biochemical assays to determine inhibitory concentrations (IC50) against NDM-1.
• In vitro synergy testing with meropenem and in vivo efficacy studies in a mouse infection model.
• Mechanistic studies to investigate enzyme-inhibitor interactions at the active site.

Main Results:

• Compound 16a exhibited potent NDM-1 inhibition with an IC50 of 3.27 μM.
• Combination therapy of 16a and meropenem demonstrated synergistic effects, reducing meropenem's minimum inhibitory concentration (MIC) 8-16 fold.
• 16a significantly suppressed NDM-1-positive bacterial growth in a mouse model of infection.
• Mechanistic studies revealed stable covalent bond formation between 16a's selenazolone warhead and NDM-1's Cys208 residue.

Conclusions:

• Covalent inhibitors based on the cephalexin scaffold are a promising strategy against NDM-1.
• Compound 16a demonstrates significant potential as an adjunct therapy to restore carbapenem efficacy.
• These findings provide valuable leads for developing new metallo-β-lactamase inhibitors.