Design, synthesis, and bioactivity investigation of novel cyclic lipopeptide antibiotics targeting top-priority multidrug-resistant gram-negative bacteria

A-Long Cui; He-Xian Yang; Hong Yi; Miao Lv; Xiao-Jiong Peng; Guang-Hui Zheng; Zhuo-Rong Li

doi:10.1016/j.ejmech.2024.116924

Design, synthesis, and bioactivity investigation of novel cyclic lipopeptide antibiotics targeting top-priority multidrug-resistant gram-negative bacteria

Eur J Med Chem. 2024 Sep 28:280:116924. doi: 10.1016/j.ejmech.2024.116924. Online ahead of print.

Authors

A-Long Cui¹, He-Xian Yang¹, Hong Yi¹, Miao Lv¹, Xiao-Jiong Peng¹, Guang-Hui Zheng², Zhuo-Rong Li³

Affiliations

¹ Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
² Laboratory of Beijing Tiantan Hospital, Capital Medical University, Beijing, 100076, China. Electronic address: [email protected].
³ Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China. Electronic address: [email protected].

PMID: 39383655
DOI: 10.1016/j.ejmech.2024.116924

Abstract

Objectives: Polymyxins are the last-line therapy for top-priority multidrug-resistant (MDR) gram-negative bacteria. However, polymyxin nephrotoxicity impedes its clinical application. This study aimed to design, synthesize, and identify a novel and promising polymyxin derivative with high efficacy and low toxicity.

Methods: To design polymyxin derivatives, we reduced the hydrophobicity of the two hydrophobic domains (fatty acyl chain and D-Phe⁶-L-Leu⁷) and modified the positive charged L-2,4-diaminobutyric acid (Dab) residues. Twenty-five derivatives were synthesized, and their antibacterial activities in vitro and renal cytotoxicities were determined. The nephrotoxicity and pharmacokinetic parameters of compound 12 were examined in rats. Antibacterial efficacy in vivo was evaluated using a mouse systemic infection model. Surface plasmon resonance analysis, compound 12-rifampicin combination therapy, and scanning electron microscopy were used to study the mechanism of action of compound 12.

Results: This research found a new compound, identified as compound 12, which showed similar or increased antibacterial activity against all tested sensitive and carbapenem-resistant gram-negative bacteria. It exhibited reduced renal cytotoxicity and nephrotoxicity, a favorable pharmacokinetic profile, and maintained or improved antibacterial efficacy in vivo. Importantly, its anti-Pseudomonas aeruginosa activity significantly improved. Compound 12, when combined with rifampicin, enhanced the activity of rifampin against gram-negative bacteria. Compound 12 also showed a high affinity for lipopolysaccharide and disrupted cell membrane integrity.

Conclusion: Reducing the hydrophobicity of the two domains reduced renal cytotoxicity and nephrotoxicity. Shortening the side chain of Dab³ by one carbon maintained or increased its antibacterial activity both in vitro and in vivo. Furthermore, only the length of the side chain of Dab⁹ could be shortened by one carbon among the Dab^1,5 and Dab^8,9 residues. The bactericidal effects of compound 12 were related to the disruption of cell membrane integrity. Compound 12 may be a promising candidate for combating sensitive and carbapenem-resistant gram-negative bacterial infections, especially Pseudomonas aeruginosa.

Keywords: Antibacterial activity; Carbapenem resistance; Cell membrane integrity; Cyclic lipopeptide antibiotics; Gram-negative bacteria; Nephrotoxicity.