Discovery of Quercetin and Its Analogs as Potent OXA-48 Beta-Lactamase Inhibitors

  • Front Pharmacol. 2022 Jun 22:13:926104. doi: 10.3389/fphar.2022.926104.
Yuejuan Zhang  1  2 ,  Cheng Chen  3 ,  Bin Cheng  4 ,  Lei Gao  1  2 ,  Chuan Qin  1  2 ,  Lixia Zhang  5 ,  Xu Zhang  1  2 ,  Jun Wang  1  2 ,  Yi Wan  1  2
Affiliations
  • 1. Microbiology Institute of Shaanxi, Xi'an, China.
  • 2. Engineering Center of Qinling Mountains Natural Products, Shaanxi Academy of Sciences, Xi'an, China.
  • 3. College of Forestry, Northwest A&F University, Yangling, China.
  • 4. MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou, China.
  • 5. Clinical Laboratory, Shaanxi Provincial People's Hospital, Xi'an, China.
PMID: 35814247 DOI: 10.3389/fphar.2022.926104
Abstract

Carbapenem resistance in Enterobacteriaceae caused by OXA-48 β-lactamase is a growing global health threat and has rapidly spread in many regions of the world. Developing inhibitors is a promising way to overcome Antibiotic resistance. However, there are few options for problematic OXA-48. Here we identified quercetin, fisetin, luteolin, 3',4',7-trihydroxyflavone, apigenin, kaempferol, and taxifolin as potent inhibitors of OXA-48 with IC50 values ranging from 0.47 to 4.54 μM. Notably, the structure-activity relationship revealed that the substitute hydroxyl groups in the A and B rings of quercetin and its structural analogs improved the inhibitory effect against OXA-48. Mechanism studies including enzymatic kinetic assay, isothermal titration calorimetry (ITC), and surface plasmon resonance (SPR) analysis demonstrated that quercetin reversibly inhibited OXA-48 through a noncompetitive mode. Molecular docking suggested that hydroxyl groups at the 3', 4' and 7 positions in Flavonoids formed hydrogen-bonding interactions with the side chains of Thr209, Ala194, and Gln193 in OXA-48. Quercetin, fisetin, luteolin, and 3',4',7-trihydroxyflavone effectively restored the Antibacterial efficacy of piperacillin or imipenem against E. coli producing OXA-48, resulting in 2-8-fold reduction in MIC. Moreover, quercetin combined with piperacillin showed antimicrobial efficacy in mice Infection model. These studies provide potential lead compounds for the development of β-lactamase inhibitors and in combination with β-lactams to combat OXA-48 producing pathogen.

Keywords
OXA-48; antibiotic resistance; flavonoid; inhibitor; quercetin; β-lactamase.
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