2. Academic Validation
  3. 2-Aminobenzothiazole based adjuvant of polymyxin E against Gram-negative bacteria

2-Aminobenzothiazole based adjuvant of polymyxin E against Gram-negative bacteria

  • Bioorg Chem. 2024 Oct 30:153:107903. doi: 10.1016/j.bioorg.2024.107903.
Yuce Chen 1,  Ping Yang 2,  Zhen Li 3,  Shuang Hou 1,  Rong Wang 1,  Jiahui Wu 4,  Zhong Li 5,  Daijie Chen 6,  Xiaoyong Xu 7
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
  • 2 Shanghai JiaoTong University, School of Pharmacy, Shanghai 200240, China; National Key Laboratory of Lead Druggability Research (Shanghai Institute of Pharmaceutical Industry Co. Ltd.), Shanghai 201203, China; Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai 200040, China.
  • 3 Shanghai JiaoTong University, School of Pharmacy, Shanghai 200240, China.
  • 4 National Key Laboratory of Lead Druggability Research (Shanghai Institute of Pharmaceutical Industry Co. Ltd.), Shanghai 201203, China.
  • 5 Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China. Electronic address: lizhong@ecust.edu.cn.
  • 6 Shanghai JiaoTong University, School of Pharmacy, Shanghai 200240, China; National Key Laboratory of Lead Druggability Research (Shanghai Institute of Pharmaceutical Industry Co. Ltd.), Shanghai 201203, China. Electronic address: chen_lab@sjtu.edu.cn.
  • 7 Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China. Electronic address: xyxu@ecust.edu.cn.
PMID: 39549489 DOI: 10.1016/j.bioorg.2024.107903
Abstract

Antibiotic resistance has emerged as a pressing global health issue. Polymyxin E, commonly regarded as a clinically important Antibiotic, faces limitations due to its dose-dependent toxicity. A crucial strategy to combat this is the development of an Antibiotic adjuvant to enhance efficacy while reducing dosage. Screening from our extensive in-house compound library, KJ1071 emerged as a promising Adjuvant candidate for polymyxin E. Subsequent structure-activity relationship studies led to the discovery of compound A35, which demonstrated superior synergistic activity. However, its limited aqueous solubility posed challenges for biological experiments. To address this, we carried out a structural derivatization aimed at enhancing its solubility. The amino acid derivative A59 notably improved aqueous solubility to 3.237 mg/mL, a substantial 3237-fold increase compared to compound A35. Moreover, A59 amplified the efficacy of polymyxin E in eradicating a variety of Gram-negative bacteria, including certain clinical strains that are resistant to polymyxin E. The mechanism studies indicated that A59 might target the Bacterial membrane. These findings suggest that the discovery of this innovative scaffold could provide critical insights for new Adjuvant therapies.

Keywords

2-Aminobenzothiazole; Acinetobacter baumannii; Antibiotic adjuvant; Aqueous solubility; Polymyxin E.

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