Rayner Beth, Verderosa Anthony D, Ferro Vito, Blaskovich Mark A T
Centre for Superbug Solutions, Institute for Molecular Bioscience, University of Queensland Brisbane Queensland Australia
Australian Infectious Disease Research Centre, The University of Queensland Brisbane Queensland Australia.
RSC Med Chem. 2023 Mar 1;14(5):800-822. doi: 10.1039/d2md00465h. eCollection 2023 May 25.
Antimicrobial resistance (AMR) is a global threat to society due to the increasing emergence of multi-drug resistant bacteria that are not susceptible to our last line of defence antibiotics. Exacerbating this issue is a severe gap in antibiotic development, with no new clinically relevant classes of antibiotics developed in the last two decades. The combination of the rapidly increasing emergence of resistance and scarcity of new antibiotics in the clinical pipeline means there is an urgent need for new efficacious treatment strategies. One promising solution, known as the 'Trojan horse' approach, hijacks the iron transport system of bacteria to deliver antibiotics directly into cells - effectively tricking bacteria into killing themselves. This transport system uses natively produced siderophores, which are small molecules with a high affinity for iron. By linking antibiotics to siderophores, to make siderophore antibiotic conjugates, the activity of existing antibiotics can potentially be reinvigorated. The success of this strategy was recently exemplified with the clinical release of cefiderocol, a cephalosporin-siderophore conjugate with potent antibacterial activity against carbapenem-resistant and multi-drug resistant Gram-negative bacilli. This review discusses the recent advancements in siderophore antibiotic conjugates and the challenges associated with the design of these compounds that need to be overcome to deliver more efficacious therapeutics. Potential strategies have also been suggested for new generations of siderophore-antibiotics with enhanced activity.
抗菌耐药性(AMR)是对社会的全球性威胁,因为多重耐药细菌的出现日益增多,这些细菌对我们最后的防线抗生素不再敏感。抗生素研发方面的严重差距使这一问题更加恶化,在过去二十年里没有开发出临床上相关的新型抗生素。耐药性迅速增加与临床研发中新型抗生素稀缺这两者结合,意味着迫切需要新的有效治疗策略。一种有前景的解决方案,即所谓的“特洛伊木马”方法,它劫持细菌的铁转运系统,将抗生素直接输送到细胞内——实际上是诱使细菌自我毁灭。这种转运系统利用天然产生的铁载体,铁载体是对铁具有高亲和力的小分子。通过将抗生素与铁载体连接,制成铁载体-抗生素结合物,现有抗生素的活性可能会得到恢复。这种策略的成功最近在头孢地尔的临床应用中得到了体现,头孢地尔是一种头孢菌素-铁载体结合物,对碳青霉烯耐药和多重耐药革兰氏阴性杆菌具有强大的抗菌活性。本文综述了铁载体-抗生素结合物的最新进展以及设计这些化合物所面临的挑战,要提供更有效的治疗方法就需要克服这些挑战。还针对具有增强活性的新一代铁载体-抗生素提出了潜在策略。