2. Academic Validation
  3. Mechanistic insights into phthalylsulfacetamide-induced restoration of meropenem bactericidal activity in NDM-1-positive Escherichia coli

Mechanistic insights into phthalylsulfacetamide-induced restoration of meropenem bactericidal activity in NDM-1-positive Escherichia coli

  • BMC Microbiol. 2026 Apr 20;26(1):521. doi: 10.1186/s12866-026-05073-w.
Xiaoting Li 1,  Wenting Liu 1,  Tao Chen 2,  Cheng Liu 1,  Zhenshu Si 1,  Yubao Li 3,  Xiuying Zhang 4
Affiliations

Affiliations

  • 1 Phage Research Center, College of Agriculture and Biology, Liaocheng University, Liaocheng, Shandong, 252000, China.
  • 2 Key Laboratory of Efficient Utilization of Non-grain Feed Resources (Co- construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Shandong Provincial Key Laboratory of Animal Nutrition and Efficient Feeding, College of Animal Science and Technology, Shandong Agricultural University, Tai'an, 271017, China.
  • 3 Phage Research Center, College of Agriculture and Biology, Liaocheng University, Liaocheng, Shandong, 252000, China. [email protected].
  • 4 Department of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang, 150030, China. [email protected].
PMID: 42010485 DOI: 10.1186/s12866-026-05073-w
Abstract

The emergence and global spread of New Delhi metallo-β-lactamase-1 (NDM-1) pose a severe threat to the efficacy of carbapenems, which are considered the last line of defense against infections caused by multidrug-resistant gram-negative bacteria. In this study, through virtual screening and enzyme activity inhibition assays, phthalylsulfacetamide (PSA) was identified as a compound exhibiting inhibitory activity against NDM-1. PSA dose-dependently inhibited NDM-1, with a 50% inhibitory concentration (IC50) of 15.4 ± 0.3 µM and an inhibition rate (IR%) of 89.2%. In vitro Antibacterial activity assays, confirmed that PSA effectively restored the Antibacterial activity of meropenem (MEM) against NDM-1-positive Escherichia. coli (E. coli), reducing the minimum inhibitory concentration (MIC) of MEM by 32-fold and demonstrating rapid bactericidal effects within 3 h. The combination of PSA and MEM had a significant synergistic effect with a fractional inhibitory concentration index (FICI) of 0.156. In vivo, the combination therapy significantly reduced the Bacterial load, decreased inflammatory cytokine levels, alleviated histopathological damage and increased survival rates in a murine systemic Infection model. Molecular dynamics simulation and site-directed mutagenesis revealed that PSA stably binds to the active hydrolysis center of NDM-1, interacts with Zn2+, and strongly interacts with the key amino acid residues Val73 and His122. Furthermore, the observed rapid bactericidal activity suggests that PSA’s mechanism of action may extend beyond NDM-1 inhibition. Molecular docking analysis indicates that PSA may potentially interact with LpxC, a key enzyme involved in lipopolysaccharide synthesis; however, this observation remains preliminary and requires further experimental validation. These results highlight PSA as a promising therapeutic agent against NDM-1-mediated carbapenem resistance.

Keywords

Carbapenem resistance; Inhibitor; NDM-1; Phthalylsulfacetamide; Synergistic effect.

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