New Multitarget Inhibitor Potentiates Antimicrobial Activity of Aztreonam against Metallo-β-lactamase-Producing...

Area of Science:

• Antimicrobial resistance
• Medicinal chemistry
• Drug discovery

Background:

• Metallo-β-lactamase (MBL)-producing Enterobacteriaceae are effectively treated with aztreonam (ATM) and avibactam (AVI).
• Pseudomonas aeruginosa (PA) exhibits complex resistance mechanisms, limiting ATM potentiation by avibactam.
• Novel strategies are needed to overcome resistance in MBL-producing PA.

Purpose of the Study:

• To identify new agents that potentiate ATM against MBL-producing PA.
• To investigate the mechanism of ATM potentiation by novel compounds.
• To evaluate the efficacy of ATM combined with novel agents against PA infections.

Main Methods:

• Screening of difluoroquercetin derivatives for ATM-potentiating activity.
• Assessing inhibition of NDM-1, OXA-10 β-lactamases, and efflux pumps by identified compounds.
• Evaluating the synergistic effect of ATM with compounds 9 and 12 against MBL-producing PA.
• Testing compound 9 in a murine thigh infection model.

Main Results:

• Compounds 9 and 12 were identified as novel ATM-potentiating agents against MBL-producing PA.
• These compounds simultaneously inhibit NDM-1, OXA-10, and efflux pumps, albeit moderately.
• Combination therapy sensitized IMP-producing CRPA to ATM, even those resistant to other MBL inhibitors.
• Compound 9 demonstrated significant in vivo ATM rescue in a murine thigh infection model.

Conclusions:

• 3,7-bis-O-substituted difluoroquercetin derivatives 9 and 12 are effective ATM-potentiating agents against MBL-producing PA.
• Simultaneous inhibition of multiple resistance mechanisms is key to potentiation.
• Compound 9 shows promise for treating infections caused by challenging multidrug-resistant PA strains.