The iron dependence of antibiotic-resistant microbes represents an Achilles’ heel that can be exploited broadly. The growing global problem of antibiotic resistance of microbial pathogens wherein microbes become resistant to the very antibiotics used against them during infection is linked not only to our health uses but also to agribusiness practices and the changing environment. Here we review mechanisms of microbial iron acquisition and host iron withdrawal defense, and the influence of iron withdrawal on the antimicrobial activity of antibiotics. Antibiotic-resistant microbes are unaltered in their iron requirements, but iron withdrawal from microbes enhances the activities of various antibiotics and importantly suppresses outgrowth of antibiotic-exposed resistant microbial survivors. Of the three therapeutic approaches available to exploit microbial iron susceptibility, including (1) use of gallium as a non-functional iron analogue, (2) Trojan horse conjugates of microbial siderophores carrying antibiotics, and (3) new generation iron chelators, purposely designed as anti-microbials, the latter offers various advantages. For instance, these novel anti-microbial chelators overcome the limitations of conventional clinically-used hematological chelators which display host toxicity and are not useful antimicrobials. 3-Hydroxypyridin-4-one-containing polymeric chelators appear to have the highest potential. DIBI (developmental code name) is a well-developed lead candidate, being a low molecular weight, water-soluble copolymer with enhanced iron binding characteristics, strong anti-microbial and anti-inflammatory activities, low toxicity for animals and demonstrated freedom from microbial resistance development. DIBI has been shown to enhance antibiotic efficacy for antibiotic-resistant microbes during infection, and it also prevents recovery growth and resistance development during microbe exposure to various antibiotics. Because DIBI bolsters innate iron withdrawal defenses of the infected host, it has potential to provide a host-directed anti-infective therapy.

耐抗生素微生物对铁的依赖是可以广泛利用的致命弱点。日益严重的全球微生物病原体抗生素耐药性问题，其中微生物在感染期间对针对它们使用的抗生素产生耐药性，这不仅与我们的健康用途有关，而且与农业综合企业实践和不断变化的环境有关。在这里，我们回顾了微生物铁获取和宿主铁戒断防御的机制，以及铁戒断对抗生素抗菌活性的影响。耐抗生素微生物对铁的需求没有改变，但从微生物中提取铁会增强各种抗生素的活性，重要的是抑制抗生素暴露的耐药微生物幸存者的生长。在利用微生物铁敏感性的三种治疗方法中，包括 (1) 使用镓作为非功能性铁类似物，(2) 携带抗生素的微生物铁载体的特洛伊木马缀合物，以及 (3) 专门设计的新一代铁螯合剂作为抗微生物剂，后者具有多种优势。例如，这些新型抗微生物螯合剂克服了常规临床使用的血液螯合剂的局限性，这些螯合剂表现出宿主毒性并且不是有用的抗微生物剂。含 3-Hydroxypyridin-4-one 的聚合物螯合剂似乎具有最高的潜力。DIBI（开发代号）是一种成熟的先导候选药物，是一种低分子量、水溶性共聚物，具有增强的铁结合特性、强大的抗微生物和抗炎活性，对动物毒性低，并证明不会产生微生物耐药性。DIBI 已被证明可在感染期间增强对抗生素抗性微生物的抗生素功效，并且它还可以防止微生物暴露于各种抗生素期间的恢复生长和耐药性发展。因为 DIBI 增强了受感染宿主的先天性铁戒断防御，它有可能提供一种宿主导向的抗感染疗法。