Siderophore–fluoroquinolone conjugates containing potential reduction-triggered linkers for drug release: synthesis and antibacterial activity
- 809 Downloads
Syntheses of two Siderophore–fluoroquinolone conjugates with a potential reduction triggered linker for drug release are described. The “trimethyl lock” based linker incorporated in the conjugates was designed to be activated by taking advantage of the reductive pathway of bacterial iron metabolism. Electrochemical and LC–MS studies indicated that the linker is thermodynamically reducible by common biological reductants and the expected lactonization proceeds rapidly with concomitant release of the drug. Antibacterial activity assays revealed that conjugates with the reduction-triggered linker were more potent than their counterparts with a stable linker, which suggests that drug release occurs inside bacterial cells.
KeywordsSiderophores Antibiotics Trojan horse Iron transport Drug delivery Drug release
Partial funding for this work was provided by NIH Grant AI054193. C. J. gratefully acknowledges the UND Chemistry-Biochemistry-Biology (CBBI) Interface Program funded by NIH (T32GM075762) for fellowship support. We gratefully acknowledge the use of the NMR facilities provided by the Lizzadro Magnetic Resonance Research Center at the University of Notre Dame (UND) under the direction of Dr. Jaroslav Zajicek and the mass spectrometry services provided by The UND Mass Spectrometry & Proteomics Facility (Mrs. N. Sevova, Dr. W. Boggess, and Dr. M. V. Joyce; supported by the National Science Foundation under CHE-0741793). We gratefully thank Mrs. Patricia A. Miller (UND) for antibacterial susceptibility testing.
- Ji C, Miller MJ (2012) Chemical syntheses and in vitro antibacterial activity of two desferrioxamine B-ciprofloxacin conjugates with potential esterase and phosphatase triggered drug release linkers. Bioorg Med Chem 20:3828–3836. doi: 10.1016/j.bmc.2012.04.034 CrossRefPubMedCentralPubMedGoogle Scholar
- Ji C, Miller PA, Miller MJ (2012b) Iron transport-mediated drug delivery: practical syntheses and in vitro antibacterial studies of tris-catecholate siderophore-aminopenicillin conjugates reveals selectively potent antipseudomonal activity. J Am Chem Soc 134:9898–9901. doi: 10.1021/ja303446w CrossRefPubMedCentralPubMedGoogle Scholar
- Wencewicz TA, Möllmann U, Long TE, Miller MJ (2009) Is drug release necessary for antimicrobial activity of siderophore-drug conjugates? Syntheses and biological studies of the naturally occurring salmycin “Trojan Horse” antibiotics and synthetic desferridanoxamine-antibiotic conjugates. Biometals 22:633–648. doi: 10.1007/s10534-009-9218-3 CrossRefPubMedCentralPubMedGoogle Scholar