Corallopyronin A: antimicrobial discovery to preclinical development

Anna K. Krome; Tim Becker; Stefan Kehraus; Andrea Schiefer; Michael Gütschow; Lillibeth Chaverra-Muñoz; Stephan Hüttel; Rolf Jansen; Marc Stadler; Alexandra Ehrens; Domen Pogorevc; Rolf Müller; Marc P. Hübner; Thomas Hesterkamp; Kenneth Pfarr; Achim Hoerauf; Karl G. Wagner; Gabriele M. König

doi:10.1039/D2NP00012A

Corallopyronin A: antimicrobial discovery to preclinical development

Anna K. Krome,

^abc Tim Becker,^ab Stefan Kehraus,^bd Andrea Schiefer,^bc Michael Gütschow,

^e Lillibeth Chaverra-Muñoz,

^f Stephan Hüttel,^f Rolf Jansen,^f Marc Stadler,

^fg Alexandra Ehrens,^bc Domen Pogorevc,

^gh Rolf Müller,

^gh Marc P. Hübner,

^bc Thomas Hesterkamp,ⁱ Kenneth Pfarr,

^bc Achim Hoerauf,^bc Karl G. Wagner

*^ab and Gabriele M. König

*^bd

Author affiliations

* Corresponding authors

^a Pharmaceutical Technology and Biopharmaceutics, University of Bonn, Germany
E-mail: karl.wagner@uni-bonn.de

^b German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, Germany

^c Institute for Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Germany

^d Institute for Pharmaceutical Biology, University of Bonn, Germany
E-mail: g.koenig@uni-bonn.de

^e Pharmaceutical & Medicinal Chemistry, University of Bonn, Germany

^f Department of Microbial Drugs, Helmholtz Centre for Infection Research, Braunschweig, Germany

^g German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Germany

^h Helmholtz Institute for Pharmaceutical Research Saarland, Saarbrucken, Germany

ⁱ Translational Project Management Office (TPMO), German Center for Infection Research (DZIF), Braunschweig, Germany

Abstract

Covering: August 1984 up to January 2022

Worldwide, increasing morbidity and mortality due to antibiotic-resistant microbial infections has been observed. Therefore, better prevention and control of infectious diseases, as well as appropriate use of approved antibacterial drugs are crucial. There is also an urgent need for the continuous development and supply of novel antibiotics. Thus, identifying new antibiotics and their further development is once again a priority of natural product research. The antibiotic corallopyronin A was discovered in the 1980s in the culture broth of the Myxobacterium Corallococcus coralloides and serves, in the context of this review, as a show case for the development of a naturally occurring antibiotic compound. The review demonstrates how a hard to obtain, barely water soluble and unstable compound such as corallopyronin A can be developed making use of sophisticated production and formulation approaches. Corallopyronin A is a bacterial DNA-dependent RNA polymerase inhibitor with a new target site and one of the few representatives of this class currently in preclinical development. Efficacy against Gram-positive and Gram-negative pathogens, e.g., Chlamydia trachomatis, Orientia tsutsugamushi, Staphylococcus aureus, and Wolbachia has been demonstrated. Due to its highly effective in vivo depletion of Wolbachia, which are essential endobacteria of most filarial nematode species, and its robust macrofilaricidal efficacy, corallopyronin A was selected as a preclinical candidate for the treatment of human filarial infections. This review highlights the discovery and production optimization approaches for corallopyronin A, as well as, recent preclinical efficacy results demonstrating a robust macrofilaricidal effect of the anti-Wolbachia candidate, and the solid formulation strategy which enhances the stability as well as the bioavailability of corallopyronin A.

Graphical abstract: Corallopyronin A: antimicrobial discovery to preclinical development

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Corallopyronin A: antimicrobial discovery to preclinical development

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