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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

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Abstract

The recent rise in drug resistance found amongst community acquired infections has sparked renewed interest in developing antimicrobial agents that target resistant organisms and limit the natural selection of immune variants. Recent discoveries have shown that iron uptake systems in bacteria and fungi are suitable targets for developing such therapeutic agents. The use of siderophore-drug conjugates as “Trojan Horse” drug delivery agents has attracted particular interest in this area. This review will discuss efforts in our research group to study the salmycin class of “Trojan Horse” antibiotics. Inspired by the natural design of the salmycins, a series of desferridanoxamine-antibiotic conjugates were synthesized and tested in microbial growth inhibition assays. The results of these studies will be related to understanding the role of drug release in siderophore-mediated drug delivery with implications for future siderophore-drug conjugate design.

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Acknowledgments

We gratefully acknowledge the National Institutes of Health (NIH) research grants RO1 AI054193, NIH AI 030988, and NIH GM025845 for financial support. We thank Irmgard Heinemann and Uta Wohlfeld for their excellent technical assistance with growth promotion and growth inhibition assays at the HKI. MJM gratefully acknowledges the kind hospitality of the HKI and the University of Notre Dame for a sabbatical opportunity in Jena, Germany. TAW gratefully acknowledges the University of Notre Dame Chemistry-Biochemistry-Biology (CBBI) Interface Program and NIH training grant T32GM075762 for a fellowship and the kind hospitality of the HKI for a research internship opportunity.

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  1. Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, 46556, USA

    Timothy A. Wencewicz, Timothy E. Long & Marvin J. Miller

  2. Department of Molecular and Applied Microbiology, Leibniz Insitute for Natural Product Research and Infection Biology—Hans-Knoell Institute, Beutenbergstrasse 11a, 07745, Jena, Germany

    Ute Möllmann

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  1. Timothy A. Wencewicz
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Correspondence to Marvin J. Miller.

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Wencewicz, T.A., Möllmann, U., Long, T.E. et al. 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 (2009). https://doi.org/10.1007/s10534-009-9218-3

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