Holbein Bruce E, Ang M Trisha C, Allan David S, Chen Wangxue, Lehmann Christian
Chelation Partners Inc., #58, The Labs at Innovacorp, Life Sciences Research Institute, 1344 Summer Street, Halifax, NS B3H OA8 Canada.
Department of Microbiology and Immunology, Dalhousie University, 5859 College St., Halifax, NS B3H 1X5 Canada.
Environ Chem Lett. 2021;19(4):2789-2808. doi: 10.1007/s10311-021-01242-7. Epub 2021 Apr 23.
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.
对抗生素耐药的微生物对铁的依赖性是一个可被广泛利用的致命弱点。微生物病原体对抗生素耐药这一日益严重的全球性问题，即微生物在感染期间对用于对抗它们的抗生素产生耐药性，不仅与我们的医疗用途有关，还与农业综合企业的做法以及不断变化的环境有关。在此，我们综述了微生物获取铁的机制、宿主铁剥夺防御以及铁剥夺对抗生素抗菌活性的影响。对抗生素耐药的微生物对铁的需求并未改变，但从微生物中剥夺铁会增强各种抗生素的活性，并且重要的是会抑制暴露于抗生素后的耐药微生物存活者的生长。在可用于利用微生物铁敏感性的三种治疗方法中，包括（1）使用镓作为无功能的铁类似物，（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）特意设计为抗菌剂的新一代铁螯合剂，后者具有多种优势。例如，这些新型抗菌螯合剂克服了传统临床使用的血液学螯合剂的局限性，后者具有宿主毒性且不是有效的抗菌剂。含3 - 羟基吡啶 - 4 - 酮的聚合物螯合剂似乎具有最高的潜力。DIBI（研发代码名称）是一个经过充分开发的先导候选物，是一种低分子量、水溶性共聚物，具有增强的铁结合特性、强大的抗菌和抗炎活性、对动物的低毒性且已证明不会产生微生物耐药性。已证明DIBI在感染期间可增强对抗生素耐药微生物的抗生素疗效，并且它还可防止微生物在接触各种抗生素期间恢复生长和产生耐药性。由于DIBI增强了受感染宿主的固有铁剥夺防御，它有潜力提供一种针对宿主的抗感染治疗方法。
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