Investigation of Siderophore–Platinum(IV) Conjugates Reveals Differing Antibacterial Activity and DNA Damage Depending on the Platinum Cargo,ACS Infectious Diseases

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Investigation of Siderophore–Platinum(IV) Conjugates Reveals Differing Antibacterial Activity and DNA Damage Depending on the Platinum Cargo
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2024-03-04 , DOI: 10.1021/acsinfecdis.3c00686
Chuchu Guo ₁ , Kwo-Kwang A Wang ₁ , Elizabeth M Nolan ₁

Affiliation

The growing threat of bacterial infections coupled with the dwindling arsenal of effective antibiotics has heightened the urgency for innovative strategies to combat bacterial pathogens, particularly Gram-negative strains, which pose a significant challenge due to their outer membrane permeability barrier. In this study, we repurpose clinically approved anticancer agents as targeted antibacterials. We report two new siderophore–platinum(IV) conjugates, both of which consist of an oxaliplatin-based Pt(IV) prodrug (oxPt(IV)) conjugated to enterobactin (Ent), a triscatecholate siderophore employed by Enterobacteriaceae for iron acquisition. We demonstrate that l/d-Ent-oxPt(IV) (l/d-EOP) are selectively delivered into the Escherichia coli cytoplasm, achieving targeted antibacterial activity, causing filamentous morphology, and leading to enhanced Pt uptake by bacterial cells but reduced Pt uptake by human cells. d-EOP exhibits enhanced potency compared to oxaliplatin and l-EOP, primarily attributed to the intrinsic antibacterial activity of its non-native siderophore moiety. To further elucidate the antibacterial activity of Ent–Pt(IV) conjugates, we probed DNA damage caused by l/d-EOP and the previously reported cisplatin-based conjugates l/d-Ent-Pt(IV) (l/d-EP). A comparative analysis of these four conjugates reveals a correlation between antibacterial activity and the ability to induce DNA damage. This work expands the scope of Pt cargos targeted to the cytoplasm of Gram-negative bacteria via Ent conjugation, provides insight into the cellular consequences of Ent–Pt(IV) conjugates in E. coli, and furthers our understanding of the potential of Pt-based therapeutics for antibacterial applications.

中文翻译：

对铁载体-铂 (IV) 缀合物的研究揭示了不同的抗菌活性和 DNA 损伤，具体取决于铂货物

细菌感染的威胁日益严重，加上有效抗生素的不断减少，迫切需要采取创新策略来对抗细菌病原体，特别是革兰氏阴性菌株，这些菌株由于其外膜渗透性屏障而构成重大挑战。在这项研究中，我们将临床批准的抗癌药物重新用作靶向抗菌药物。我们报告了两种新的铁载体-铂（IV）缀合物，两者均由与肠杆菌素（Ent）缀合的基于奥沙利铂的Pt（IV）前药（oxPt（IV））组成，肠杆菌素是肠杆菌科用于获取铁的三儿茶酚酸铁载体。我们证明l / d -Ent-oxPt（IV）（ l / d -EOP）选择性地递送到大肠杆菌细胞质中，实现靶向抗菌活性，形成丝状形态，并导致细菌细胞对Pt的吸收增强，但减少人体细胞对 Pt 的吸收。与奥沙利铂和l -EOP 相比， d -EOP 表现出增强的效力，这主要归因于其非天然铁载体部分的内在抗菌活性。为了进一步阐明 Ent–Pt(IV) 缀合物的抗菌活性，我们探测了l / d -EOP 和之前报道的基于顺铂的缀合物l / d -Ent-Pt(IV) ( l / d -EP) 引起的 DNA 损伤。）。对这四种缀合物的比较分析揭示了抗菌活性和诱导 DNA 损伤的能力之间的相关性。这项工作扩大了通过 Ent 缀合靶向革兰氏阴性细菌细胞质的 Pt 货物的范围，深入了解 Ent-Pt(IV) 缀合物在大肠杆菌中的细胞后果，并进一步加深了我们对 Pt- 潜力的理解。基于抗菌应用的疗法。

更新日期：2024-03-04

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