Miao Zhi-Ying, Lin Jing, Chen Wei-Min
State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, Guangzhou, 511400, China.
State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, Guangzhou, 511400, China.
Eur J Med Chem. 2025 Apr 5;287:117333. doi: 10.1016/j.ejmech.2025.117333. Epub 2025 Jan 28.
The widespread emergence of multidrug-resistant (MDR) Gram-negative pathogens has posed a major challenge to clinical anti-infective therapy, and new effective treatments are urgently needed. A promising "Trojan horse" strategy involves conjugating antibiotics to siderophore molecules; the resulting siderophore-antibiotic conjugates (SACs) deliver antibiotics directly into cells by hijacking the sophisticated iron transport systems of Gram-negative bacteria, bypassing the outer membrane permeability barrier to enhance uptake and antibacterial efficacy. The clinical release of the first siderophore-antibiotic conjugate, cefiderocol, has aroused tremendous interest in the field among researchers and pharmaceutical companies. To date, most of the reported SACs have focused on the conjugation of siderophores to traditional antibacterial drugs. However, these antibacterial agents designed on the basis of the traditional antibiotic skeleton theoretically bear the risk of cross-resistance caused by shared molecular scaffolds. In this case, exploring novel natural product antibacterial conjugate scaffolds to circumvent the risk of early cross-resistance represents a presumably more sustainable approach for the development of SACs. In this review, we systematically summarize the research progress on siderophore-natural product conjugates as novel antimicrobial agents reported since 2010. Additionally, we propose challenges to be overcome and prospects for future development in this field.
多重耐药（MDR）革兰氏阴性病原体的广泛出现给临床抗感染治疗带来了重大挑战，因此迫切需要新的有效治疗方法。一种有前景的“特洛伊木马”策略是将抗生素与铁载体分子结合；由此产生的铁载体-抗生素共轭物（SAC）通过劫持革兰氏阴性菌复杂的铁转运系统将抗生素直接输送到细胞中，绕过外膜通透性屏障以增强摄取和抗菌效果。首个铁载体-抗生素共轭物头孢地尔的临床上市引起了该领域研究人员和制药公司的极大兴趣。迄今为止，大多数报道的SAC都集中在铁载体与传统抗菌药物的结合上。然而，这些基于传统抗生素骨架设计的抗菌剂理论上存在因共享分子支架而导致交叉耐药的风险。在这种情况下，探索新型天然产物抗菌共轭物支架以规避早期交叉耐药风险，可能是开发SAC更具可持续性的方法。在这篇综述中，我们系统地总结了自2010年以来报道的作为新型抗菌剂的铁载体-天然产物共轭物的研究进展。此外，我们还提出了该领域需要克服的挑战和未来发展的前景。
