Antibiotic conjugates: Using molecular Trojan Horses to overcome drug resistance
Xi Li, Siyuan Dong, Qi Pan, Ning Liu, Yijie Zhang
Abstract
Antimicrobial resistance (AMR) has become a global health crisis due to the rapid emergence of multi-drug-resistant bacteria. The paucity of novel antibiotics in the clinical pipeline has exacerbated this issue, thereby warranting the development of new antibacterial therapies. The 'Trojan Horse' strategy entails conjugating antibiotics with bioactive components that not only facilitate the entry of antibiotic molecules into bacterial cells by circumventing the membrane barriers, but also augment the effects of conventional antibiotics against recalcitrant pathogens. These Trojan Horse elements can also serve as a promising tool for repurposing drugs with hitherto unexamined antimicrobial activity, or drugs with limited clinical utility due to considerable toxic side effects. In this review, we have discussed the current state of research on antibiotic conjugates with monoclonal antibodies (mAbs), antimicrobial peptides (AMPs) and the iron-chelating siderophores. The rationale and mechanisms of different antibiotic conjugates have been summarized, and the preclinical and clinical evidence pertaining to the activity of these conjugates against drug-resistant pathogens have been reviewed. Furthermore, the challenges associated with the clinical translation of these novel antimicrobials, and the future research directions have also been discussed. While antibiotic conjugates offer an attractive alternative to conventional antimicrobials, there are several obstacles to their clinical translation. A greater understanding of the mechanisms underlying AMR, and continuing advances in genetic engineering, synthetic biology, and bioinformatics will be crucial in designing more selective, potent, and safe antibiotic conjugates for tackling multi-drug resistant (MDR) infections.