A Salmochelin S4-inspired Ciprofloxacin Trojan Horse Conjugate

TY - JOUR

T1 - A Salmochelin S4-inspired Ciprofloxacin Trojan Horse Conjugate

AU - Sanderson, Thomas

AU - Black, Conor

AU - Southwell, James

AU - Wilde, Ellis

AU - Pandey, Apurva

AU - Herman, Reyme

AU - Thomas, Gavin H

AU - Boros, Eszter

AU - Duhme-Klair, Anne Kathrin

AU - Routledge, Anne

N1 - © 2020 American Chemical Society. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.

PY - 2020/9/11

Y1 - 2020/9/11

N2 - A novel ciprofloxacin-siderophore Trojan Horse antimicrobial was prepared by incorporating key design features of salmochelin S4, a stealth siderophore that evades mammalian siderocalin capture via its glycosylated catechol units. As-sessment of the antimicrobial activity of the conjugate revealed that attachment of the salmochelin mimic resulted in decreased potency, compared to ciprofloxacin, against two Escherichia coli strains, K12 and Nissle 1917, in both iron-replete and deplete conditions. This observation could be attributed to a combination of reduced DNA gyrase inhibi-tion, as confirmed by in vitro DNA gyrase assays, and reduced bacterial uptake. Uptake was monitored using radio-labelling with iron-mimetic 67Ga3+, which revealed limited cellular uptake in E. coli K12. In contrast, previously reported staphyloferrin-based conjugates displayed measurable uptake in analogous 67Ga3+, labelling studies. These results suggest that in designing Trojan Horse antimicrobials, the choice of siderophore and the nature and length of the link-er remains a significant challenge.

AB - A novel ciprofloxacin-siderophore Trojan Horse antimicrobial was prepared by incorporating key design features of salmochelin S4, a stealth siderophore that evades mammalian siderocalin capture via its glycosylated catechol units. As-sessment of the antimicrobial activity of the conjugate revealed that attachment of the salmochelin mimic resulted in decreased potency, compared to ciprofloxacin, against two Escherichia coli strains, K12 and Nissle 1917, in both iron-replete and deplete conditions. This observation could be attributed to a combination of reduced DNA gyrase inhibi-tion, as confirmed by in vitro DNA gyrase assays, and reduced bacterial uptake. Uptake was monitored using radio-labelling with iron-mimetic 67Ga3+, which revealed limited cellular uptake in E. coli K12. In contrast, previously reported staphyloferrin-based conjugates displayed measurable uptake in analogous 67Ga3+, labelling studies. These results suggest that in designing Trojan Horse antimicrobials, the choice of siderophore and the nature and length of the link-er remains a significant challenge.

U2 - 10.1021/acsinfecdis.0c00568

DO - 10.1021/acsinfecdis.0c00568

M3 - Article

C2 - 32786274

SN - 2373-8227

VL - 6

SP - 2532

EP - 2541

JO - ACS Infectious Diseases

JF - ACS Infectious Diseases

IS - 9

ER -