Natural sideromycins and siderophore-conjugated natural products as inspiration for novel antimicrobial agents

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.