Design, solid-phase synthesis and evaluation of enterobactin analogs for iron delivery into the human pathogen Campylobacter jejuni

Abstract

The human enteropathogen Campylobacter jejuni, like many bacteria, employs siderophores such as enterobactin for cellular uptake of ferric iron. This transport process has been shown to be essential for virulence and presents an attractive opportunity for further study of the permissiveness of this pathway to small-molecule intervention and as inspiration for the development of synthetic carriers that may effectively transport cargo into Gram-negative bacteria. In this work, we have developed a facile and robust microscale assay to measure growth recovery of C. jejuni NCTC 11168 in liquid culture as a result of ferric iron uptake. In parallel, we have established the solid-phase synthesis of catecholamide compounds modeled on enterobactin fragments. Applying these methodological developments, we show that small synthetic iron chelators of minimal dimensions provide ferric iron to C. jejuni with equal or greater efficiency than enterobactin.

Mimicking salmochelin S1 and the interactions of its Fe(III) complex with periplasmic iron siderophore binding proteins CeuE and VctP

“…34 and the finding that bisDHBS is a functional Fe(III) uptake mediator in C. jejuni. 55 Our results suggest that the role of the tetradentate stealth siderophore salmochelin S1 in the iron uptake of enteric pathogens merits further investigation as it may be of importance in iron cross-feeding within environments that are shared with salmochelin-producing E. coli strains, for example inflamed mammalian small intestines. 56 Salmochelin S1 utilisation may provide scavenging pathogenic species with a competitive advantage in microbiota where the Fe(III) complexes of enterobactin and vibriobactin are being removed by the innate defence protein siderocalin, whilst glucosylated stealth siderophore, such as salmochelin S1, evade capture.…”

Biomimetic enterobactin analogue mediates iron-uptake and cargo transport into E. coli and P. aeruginosa

“…17,19 Previously reported articial Ent analogues used for the development of siderophore drug conjugates or siderophore-based imaging tools 71,72 were based on modications at one of the catechol units 42,43,46,49,52,[73][74][75] or the natural tris-serine lactone backbone was substituted by articial moieties to generate an attachment point for payloads in the backbone of the siderophore. 48,[76][77][78] Although a co-crystal structure of [Fe-Ent] 3À with its E. coli siderophore receptors of FepA 79,80 and IroN [80][81][82] is not available, recognition of [Fe-Ent] 3À at other proteins such as FeuA, [83][84][85] VctP, 86 PfeA 69 or lipocalin-2 (ref. 83 ) suggests that the attachment of larger payloads at the catechol units might interfere with [Fe-Ent] 3À receptor recognition.…”

Meeting Proceedings from ICBS 2018—Toward Translational Impact

“…She uncovered the multifaceted importance of the Pgl pathway in C. jejuni host–pathogen interactions and characterized the importance of chemokine and cytokines profiles and the different composition of virulence-associated outer-membrane vesicles in pathogenesis. She identified how N-glycans participate in invasion and affect vesicle composition, properties that might be important for the development of novel therapeutic strategies against this bacteria …”

“…She identified how N-glycans participate in invasion and affect vesicle composition, properties that might be important for the development of novel therapeutic strategies against this bacteria. 23 Open Panel Discussion: Academic/Industry Partnerships to Promote Drug Discovery through Chemical Biology. Rathnam Chaguturu (iDDPartners, USA) chaired the discussion with seven panel members: Doug Auld (Novartis, USA), Scott Wolkenberg (Merck, USA), Melvin Reichman (Lankenau Institute, USA), Haian Fu (Emory University, USA), Shaomeng Wang (University of Michigan, USA), Rima Al-Awar (Ontario Institute of Cancer Research, Canada), and Yves Auberon (Novartis/EFMC, Switzerland).…”