Structure-Directed Optimization of Ebselen Derivatives as Potent NDM-1 Inhibitors Reverses Meropenem Resistance

Area of Science:

• Medicinal Chemistry
• Microbiology
• Drug Discovery

Background:

• The global spread of New Delhi metallo-β-lactamase-1 (NDM-1) compromises the effectiveness of essential β-lactam antibiotics.
• Urgent development of NDM-1 inhibitors is crucial to combat NDM-1-mediated bacterial resistance.

Purpose of the Study:

• To design and synthesize novel NDM-1 inhibitors.
• To evaluate the efficacy of these inhibitors in restoring antibiotic activity against NDM-1-producing bacteria.

Main Methods:

• Ebselen was used as a lead compound for designing 59 novel derivatives.
• In vitro enzyme inhibition assays determined the potency of compounds against NDM-1.
• Minimum Inhibitory Concentration (MIC) assays assessed the synergistic effect of compound 27k with meropenem (Mem).
• In vivo studies in mice evaluated the efficacy of the combination therapy.

Main Results:

• Compound 27k exhibited potent NDM-1 inhibition with an IC50 of 1.12 μM.
• Combination of 27k and Mem reduced meropenem MIC by 4-16 fold in NDM-1 isolates.
• 27k and Mem combination significantly suppressed bacterial loads in a mouse model.
• Compound 27k covalently binds to NDM-1 via a Se-S bond, inhibiting its activity.

Conclusions:

• Compound 27k is a potent covalent inhibitor of NDM-1.
• 27k demonstrates potential as a lead compound to overcome NDM-1-mediated antibiotic resistance.
• This discovery offers a promising strategy to restore the clinical utility of β-lactam antibiotics.