Development of Polymyxin Analogs with Expanded Activity Against Both Gram-Positive and Gram-Negative Bacteria

doi:10.7503/cjcu20260214

Chem. J. Chinese Universities

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Development of Polymyxin Analogs with Expanded Activity Against Both Gram-Positive and Gram-Negative Bacteria

MA Wenjie^1*, ZHANG Bing³, WANG Jiaqi², BLASCO Pilar², GAO Peng⁴, XU Jianchao⁵, CHEN Sheng^3*, LI Xuechen^1,2*

1. Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences 2. State Key Laboratory of Synthetic Chemistry, Department of Chemistry, The University of Hong Kong 3. State Key Laboratory of Chemical Biology and Drug Discovery, Department of Food Science and Nutrition, The Hong Kong Polytechnic University 4. Applied Oral Sciences & Community Dental Care, Faculty of Dentistry, The University of Hong Kong 5. Suzhou NexTide Co., Ltd.

Received:2026-05-24 Revised:2026-06-17 Online First:2026-06-21 Published:2026-06-21
Supported by:
Supported by the National Natural Science Foundation of China(No. 22507135) and the Research Grants Council of Hong Kong(No. JLFS/P-404/24)

Abstract

Abstract: The increasing threat of bacterial infections has created an urgent need for novel antibiotics. Herein, we report a novel polymyxin analog, PL-082, modified at its N-terminal lipid and first amino acid. Distinct from conventional polymyxins, which are exclusively active against Gram-negative bacteria, PL-082 exhibits expanded antibacterial activity against both Gram-positive and Gram-negative bacteria. Through NMR and molecular dynamics simulations, we reveal that the strong interactions between PL-082 and POPG phospholipids—a dominant component of Gram-positive bacterial membrane—account for its unique activity against Gram-positive bacteria. Beyond elucidating the antibacterial mechanism of the novel antibiotic PL-082, this work also provides promising avenues for the development of potent, broad-spectrum antibiotics.

Key words: Polymyxin analog, Gram-positive bacteria, POPG phospholipids

CLC Number:

O629.72

TrendMD:

MA Wenjie, ZHANG Bing, WANG Jiaqi, BLASCO Pilar, GAO Peng, XU Jianchao, CHEN Sheng, LI Xuechen. Development of Polymyxin Analogs with Expanded Activity Against Both Gram-Positive and Gram-Negative Bacteria[J]. Chem. J. Chinese Universities, doi: 10.7503/cjcu20260214.

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Development of Polymyxin Analogs with Expanded Activity Against Both Gram-Positive and Gram-Negative Bacteria

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