Conjugation to Enterobactin and Salmochelin S4 Enhances the Antimicrobial Activity and Selectivity of β-Lactam Antibiotics against Nontyphoidal Salmonella.
Conjugation to Enterobactin and Salmochelin S4 Enhances the Antimicrobial Activity and Selectivity of β-Lactam Antibiotics against Nontyphoidal Salmonella.
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DOI：
10.1021/acsinfecdis.1c00005
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发表时间：
2021-05-14
影响因子：
5.3
通讯作者：
Nolan EM
中科院分区：
文献类型：
--
作者：
Sargun A;Sassone-Corsi M;Zheng T;Raffatellu M;Nolan EM
病原体肠道沙门氏菌是全球感染的主要原因。非伤寒沙门氏菌（NTS）血清型通常引起健康个体的炎性腹泻，并可引起免疫功能低下患者、儿童和老年人的菌血症。NTS感染的管理是一个挑战，因为抗生素治疗阻止病原体的粪便脱落，因此不推荐用于大多数患者。近年来，抗生素耐药性在NTS中的出现也成为一个主要问题。因此，需要新的治疗策略来靶向NTS。在这里，我们评估了基于肠杆菌素（Ent）和沙门氏菌螯铁蛋白S4（双糖基化Ent，DGE）的六种铁载体-β-内酰胺缀合物是否通过靶向铁载体受体FepA和IroN对两种高度流行的NTS血清型鼠伤寒和肠杆菌提供抗微生物活性。在铁限制条件下，与母体抗生素相比，缀合物对鼠伤寒和肠杆菌血清型的最低抑制浓度低10至1，000倍，并被FepA和/或IroN识别和转运。用Ent/DGE-β-内酰胺缀合物处理的NTS表现出异常的细胞形态，表明青霉素结合蛋白的抑制，并且缀合物选择性地杀死与金黄色葡萄球菌共培养的NTS。最后，基于DGE的缀合物被证明在ENT螯合蛋白脂质运载蛋白-2的存在下有效抑制NTS的生长。这项工作描述了成功使用铁载体-抗生素缀合物对NTS，并强调了通过使用Ent和DGE靶向肠道细菌病原体来缩小抗生素活性谱的机会。基于肠杆菌素（Ent）和二葡糖基化肠杆菌素（DGE）的铁载体-β-内酰胺缀合物通过FepA和/或IroN转运蛋白进入非伤寒性肠道沙门氏菌血清型鼠伤寒和肠杆菌的周质，并靶向周质中的青霉素结合蛋白。
The pathogen Salmonella enterica is a leading cause of infection worldwide. Non-typhoidal Salmonella (NTS) serovars typically cause inflammatory diarrhea in healthy individuals, and can cause bacteremia in immunocompromised patients, children and the elderly. Management of NTS infection poses a challenge because antibiotic treatment prolongs fecal shedding of the pathogen and is thus not recommended for most patients. In recent years, the emergence of antibiotic resistance in NTS has also become a major issue. Thus, new therapeutic strategies to target NTS are needed. Here, we evaluated whether six siderophore-β-lactam conjugates based on enterobactin (Ent) and salmochelin S4 (digulcosylated Ent, DGE) provide antimicrobial activity against the two highly prevalent NTS serovars Typhimurium and Enteritidis by targeting the siderophore receptors FepA and IroN. The conjugates showed 10- to 1,000-fold lower minimum inhibitory concentrations against both serovars Typhimurium and Enteritidis compared to the parent antibiotics under iron limitation and were recognized and transported by FepA and/or IroN. NTS treated with the Ent/DGE-β-lactam conjugates exhibited aberrant cellular morphologies suggesting inhibition of penicillin-binding proteins, and the conjugates selectively killed NTS in co-culture with Staphylococcus aureus. Lastly, the DGE-based conjugates proved to be effective at inhibiting growth of NTS in the presence of the Ent-sequestering protein lipocalin-2. This work describes the successful use of siderophore-antibiotic conjugates against NTS and highlights the opportunity for narrowing the activity spectrum of antibiotics by using Ent and DGE to target enteric bacterial pathogens. Siderophore-β-lactam conjugates based on enterobactin (Ent) and diglucosylated enterobactin (DGE) enter the periplasm of non-typhoidal Salmonella enterica serovars Typhimurium and Enteritidis via the FepA and/or IroN transporters, and target penicillin-binding proteins in the periplasm.
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影响因子：
3.2
作者：
ERNST, JF;BENNETT, RL;ROTHFIELD, LI
通讯作者：
ROTHFIELD, LI
DOI：
10.1073/pnas.0737682100
发表时间：
2003-04-01
影响因子：
11.1
作者：
Hantke, K;Nicholson, G;Winkelmann, G
通讯作者：
Winkelmann, G
影响因子：
5.5
作者：
Kariuki S;Gordon MA;Feasey N;Parry CM
通讯作者：
Parry CM
DOI：
10.1073/pnas.0510847103
发表时间：
2006-02-07
影响因子：
11.1
作者：
Berger, T;Togawa, A;Mak, TW
通讯作者：
Mak, TW
影响因子：
16
作者：
Goetz, DH;Holmes, MA;Strong, RK
通讯作者：
Strong, RK