New Multitarget Inhibitor Potentiates Antimicrobial Activity of Aztreonam against Metallo-β-lactamase-Producing Pseudomonas aeruginosa Including IMP-Types

  • J Med Chem. 2026 Mar 12;69(5):5560-5574. doi: 10.1021/acs.jmedchem.5c02664.
Jihyeok Kang  1 ,  Dahee Lee  1 ,  Mi Kyoung Kim  1 ,  Joong Hoon Ahn  1 ,  Tae-Won Kim  2 ,  Jisun Park  3 ,  Hwi Won Seo  3 ,  Tae Kun Ahn  4 ,  Eun Kyoung Chung  5 ,  Ki-Ho Park  6 ,  Youhoon Chong  1
Affiliations
  • 1. Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Neungdong-ro 120, Gwangjin-gu, Seoul 05029, Korea.
  • 2. College of Veterinary Medicine (BK21 FOUR Program), Chungnam National University, 99 Daehak-ro, Daejeon 34131, Republic of Korea.
  • 3. Infectious Disease Research Center, Korea Research Institute of Bioscience & Biotechnology, Daejeon 34141, Korea.
  • 4. Department of Regulatory Science, Institutes of Regulatory Innovation through Science and Integrated Pharmaceutical Sciences, College of Pharmacy, Kyung Hee University, Seoul 02447, Korea.
  • 5. Departments of Pharmacy and Regulatory Science, Institutes of Regulatory Innovation through Science (IRIS) and Integrated Pharmaceutical Sciences, College of Pharmacy, Kyung Hee University, Seoul 02447, Korea.
  • 6. Department of Infectious Disease, Kyung Hee University School of Medicine, Seoul 02447, Republic of Korea.
PMID: 41773615 DOI: 10.1021/acs.jmedchem.5c02664
Abstract

Combination of aztreonam (ATM) and avibactam (AVI) was proven to be synergistic against Metallo-β-lactamase (MBL)-producing Enterobacteriaceae. However, in the case of Pseudomonas aeruginosa (PA), ATM-potentiation by AVI can hardly be achieved because PA has complex resistance mechanisms. In this study, we identified 3,7-bis-O-substituted difluoroquercetin derivatives 9 and 12 as new ATM-potentiating agents against the MBL-producing PAs through the simultaneous inhibition of NDM-1, OXA-10, and efflux pumps. Even though the inhibitory activity of 9 and 12 against the ATM-hydrolyzing β-lactamases (NDM-1 and OXA-10) as well as the efflux pumps is moderate, the simultaneous inhibition of multiple resistance mechanisms seems to result in remarkable potentiation of ATM against this formidable pathogen. Particularly, the IMP-producing CRPAs resistant to the most promising MBL-inhibitors were sensitized to ATM upon combination with compounds 9 and 12. Compound 9 demonstrated potent in vivo rescue of ATM activity in a murine thigh Infection model.

Products