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Synthetic sideromycins (skepticism and optimism): selective generation of either broad or narrow spectrum Gram-negative antibiotics

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Abstract

New or repurposed antibiotics are desperately needed since bacterial resistance has risen to essentially all of our current antibiotics, and few new antibiotics have been developed over the last several decades. A primary cause of drug resistance is the overuse of antibiotics that can result in alteration of microbial permeability, alteration of drug target binding sites, induction of enzymes that destroy antibiotics (i.e., β-lactamases) and even induction of efflux mechanisms. Research efforts are described that are designed to determine if the known critical dependence of iron assimilation by microbes for growth and virulence can be exploited for the development of new approaches to antibiotic therapy. Iron recognition and active transport relies on the biosyntheses and use of microbe-selective iron chelating compounds called siderophores. Several natural siderophore-antibiotic conjugates (sideromycins) have been discovered and studied. The natural sideromycins consist of an iron binding siderophore linked to a warhead that exerts antibiotic activity once assimilated by targeted bacteria. Inspired these natural conjugates, a combination of chemical syntheses, microbiological and biochemical studies have been used to generate semi-synthetic and totally synthetic sideromycin analogs. The results demonstrate that siderophores and analogs can be used for iron transport-mediated drug delivery (“Trojan Horse” antibiotics or sideromycins) and induction of iron limitation/starvation (development of new agents to block iron assimilation). While several examples illustrate that this approach can generate microbe selective antibiotics that are active in vitro, the scope and limitations of this approach, especially related to development of resistance, siderophore based molecular recognition requirements, appropriate linker and drug choices, will be described.

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Acknowledgements

Early support for the authors’ siderophore and sideromycin studies at the University of Notre Dame was provided by the NIH. Subsequent support through Hsiri Therapeutics was provided by the Department of Defense (W81XWH-12-2-0015) and through the generosity of Dr. William Claypool. MJM thanks all the coworkers at the University of Notre Dame and collaborators world-wide throughout the years for all the interest in siderophores, sideromycins and related studies.

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  1. Hsiri Therapeutics, Rosetree Corporate Center, 1400 N. Providence Road, Building 1, Suite 115S, Media, PA, 19063, USA

    Yun-Ming Lin, Manuka Ghosh, Patricia A. Miller, Ute Möllmann & Marvin J. Miller

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

    Marvin J. Miller

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  1. Yun-Ming Lin
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  2. Manuka Ghosh
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  3. Patricia A. Miller
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  4. Ute Möllmann
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  5. Marvin J. Miller
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Correspondence to Marvin J. Miller.

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Lin, YM., Ghosh, M., Miller, P.A. et al. Synthetic sideromycins (skepticism and optimism): selective generation of either broad or narrow spectrum Gram-negative antibiotics. Biometals 32, 425–451 (2019). https://doi.org/10.1007/s10534-019-00192-6

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  • DOI: https://doi.org/10.1007/s10534-019-00192-6

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