Related Experiment Video
Updated: Jan 21, 2026
Identifying PD-1/PD-L1 Inhibitors with Surface Plasmon Resonance Technology
Published on: May 2, 2025
Design, Synthesis and Biological Evaluation of 1-Phenyl-2-(phenylamino) Ethanone Derivatives as Novel MCR-1
Xiu-Juan Lan1,2,3, Hai-Tao Yan3, Feng Lin4
1School of Pharmaceutical Sciences, Jilin University, Changchun 130021, China.
Abstract:
Polymyxins are considered to be the last-line antibiotics that are used to treat infections caused by multidrug-resistant (MDR) gram-negative bacteria; however, the plasmid-mediated transferable colistin resistance gene (mcr-1) has rendered polymyxins ineffective. Therefore, the protein encoded by mcr-1, MCR-1, could be a target for structure-based design of inhibitors to tackle polymyxins resistance. Here, we identified racemic compound 3 as a potential MCR-1 inhibitor by virtual screening, and 26 compound 3 derivatives were synthesized and evaluated in vitro. In the cell-based assay, compound 6g, 6h, 6i, 6n, 6p, 6q, and 6r displayed more potent activity than compound 3. Notably, 25 μΜ of compound 6p or 6q combined with 2 μg·mL-1 colistin could completely inhibit the growth of BL21(DE3) expressing mcr-1, which exhibited the most potent activity. In the enzymatic assay, we elucidate that 6p and 6q could target the MCR-1 to inhibit the activity of the protein. Additionally, a molecular docking study showed that 6p and 6q could interact with Glu246 and Thr285 via hydrogen bonds and occupy well the cavity of the MCR-1 protein. These results may provide a potential avenue to overcome colistin resistance, and provide some valuable information for further investigation on MCR-1 inhibitors.
Insights
New compounds show promise in combating colistin resistance. Specifically, compounds 6p and 6q effectively inhibited the MCR-1 protein, a key factor in multidrug-resistant bacterial infections.
Area of Science:
- Medicinal Chemistry
- Microbiology
- Drug Discovery
Background:
- Polymyxins are last-resort antibiotics against multidrug-resistant (MDR) gram-negative bacteria.
- The emergence of the mcr-1 gene confers resistance to colistin, a critical polymyxin.
- The MCR-1 protein is a potential target for developing novel inhibitors to overcome resistance.
Purpose of the Study:
- To identify and synthesize potential inhibitors of the MCR-1 protein.
- To evaluate the efficacy of synthesized compounds against MCR-1 mediated colistin resistance.
- To provide insights for developing new strategies against MDR bacterial infections.
Main Methods:
- Virtual screening to identify lead compound 3.
- Synthesis and in vitro evaluation of 26 derivatives of compound 3.
- Cell-based and enzymatic assays to determine inhibitory activity against MCR-1.
- Molecular docking studies to elucidate binding interactions.
Main Results:
- Compounds 6g, 6h, 6i, 6n, 6p, 6q, and 6r showed enhanced activity compared to compound 3.
- Compounds 6p and 6q, at 25 μM, completely inhibited bacterial growth when combined with colistin.
- Enzymatic assays confirmed that 6p and 6q inhibit MCR-1 activity.
- Molecular docking revealed hydrogen bonding interactions of 6p and 6q with MCR-1 residues Glu246 and Thr285.
Conclusions:
- Compounds 6p and 6q are potent inhibitors of the MCR-1 protein.
- These compounds represent a potential strategy to overcome colistin resistance.
- Further investigation into MCR-1 inhibitors is warranted based on these findings.
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