Targeting the Class A Carbapenemase GES-5 via Virtual Screening

Area of Science:

• Microbiology
• Medicinal Chemistry
• Drug Discovery

Background:

• The rise of β-lactamases that degrade carbapenems fuels antibiotic resistance, threatening effective treatment of bacterial infections.
• GES-type carbapenemases, unlike KPC-type, currently lack therapeutic inhibitors, highlighting them as critical drug targets.

Purpose of the Study:

• To identify novel inhibitors for GES carbapenemases, specifically targeting the prevalent GES-5 variant.
• To provide starting points for developing new antimicrobial therapies against carbapenem-resistant bacteria.

Main Methods:

• In silico screening of a lead-like compound library against the GES-5 carbapenemase structure.
• In vitro biochemical assays to validate inhibitory activity of selected compounds against recombinant GES-5.
• Evaluation of the best inhibitors against KPC-2 carbapenemase.

Main Results:

• Identified four derivatives exhibiting high micromolar competitive inhibition against GES-5.
• The most potent inhibitors demonstrated activity against both GES-5 and KPC-2 carbapenemases.
• The study successfully generated promising hit compounds for further drug development.

Conclusions:

• The identified inhibitors represent valuable starting points for hit-to-lead optimization against GES carbapenemases.
• This research contributes to the urgent need for new therapeutic strategies against antibiotic-resistant pathogens.
• Targeting GES enzymes offers a viable approach to combatting carbapenem resistance.