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Sideromycins as Pathogen-Targeted Antibiotics

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Antibacterials

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 26))

Abstract

The overuse of broad-spectrum antibiotics rapidly selects for dangerous multi-drug resistant bacterial pathogens. The landscape of antibiotic drug discovery is adapting to this wave of resistance with a movement towards narrow-spectrum, pathogen-targeted antibiotics that limit the emergence of new resistance. Sideromycins (siderophore-antibiotic conjugates) exploit essential iron acquisition pathways to achieve receptor-mediated cell entry where the spectrum of antibiotic activity is determined by highly selective cell surface siderophore receptors rather than the widely distributed and highly conserved antibacterial target. Sideromycins overwhelm traditional resistance mechanisms through high intracellular antibiotic concentrations and resistance adaptation renders pathogens avirulent. The timing is optimal to pursue sideromycins as pathogen-targeted antibiotics and chemical probes for rapid pathogen diagnostics.

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Acknowledgments

MJM thanks all group members and collaborators who worked on the synthesis and study of siderophores and sideromycins in his research laboratory at the University of Notre Dame over the past 40 years (1977–2017) with near continuous support from the NIH. MJM and TAW sincerely thank Dr. Ute Möllmann (Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute) for years of friendship and collaboration on siderophore microbiology. TAW acknowledges the NSF for a CAREER Award (1654611) that supports siderophore research in his laboratory.

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  1. Department of Chemistry, Washington University in St. Louis, One Brookings Drive, St. Louis, MO, 63130, USA

    Timothy A. Wencewicz

  2. Department of Chemistry and Biochemistry, University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, IN, 46556, USA

    Marvin J. Miller

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  1. Timothy A. Wencewicz
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Correspondence to Timothy A. Wencewicz .

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  1. Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA

    Jed F. Fisher

  2. Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA

    Shahriar Mobashery

  3. Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA

    Marvin J. Miller

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Wencewicz, T.A., Miller, M.J. (2017). Sideromycins as Pathogen-Targeted Antibiotics. In: Fisher, J., Mobashery, S., Miller, M. (eds) Antibacterials. Topics in Medicinal Chemistry, vol 26. Springer, Cham. https://doi.org/10.1007/7355_2017_19

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