Amidochelocardin Overcomes Resistance Mechanisms Exerted on Tetracyclines and Natural Chelocardin.

Fabienne Hennessen,Nestor Zaburannyi,Steffen Bernecker,Florian Wagenlehner,Maria Loose,Alexander J Westermann,Judith Schmiedel,Marcus Miethke,Thomas Hesterkamp,Rolf Müller,Can Imirzalioglu,Rolf Jansen,Stephan Hüttel,Tadeja Lukežič,Jennifer Herrmann,Hrvoje Petković,Jörg Vogel,Moritz Fritzenwanker,Marc Stadler

doi:10.3390/antibiotics9090619

Abstract

The reassessment of known but neglected natural compounds is a vital strategy for providing novel lead structures urgently needed to overcome antimicrobial resistance. Scaffolds with resistance-breaking properties represent the most promising candidates for a successful translation into future therapeutics. Our study focuses on chelocardin, a member of the atypical tetracyclines, and its bioengineered derivative amidochelocardin, both showing broad-spectrum antibacterial activity within the ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) panel. Further lead development of chelocardins requires extensive biological and chemical profiling to achieve favorable pharmaceutical properties and efficacy. This study shows that both molecules possess resistance-breaking properties enabling the escape from most common tetracycline resistance mechanisms. Further, we show that these compounds are potent candidates for treatment of urinary tract infections due to their in vitro activity against a large panel of multidrug-resistant uropathogenic clinical isolates. In addition, the mechanism of resistance to natural chelocardin was identified as relying on efflux processes, both in the chelocardin producer Amycolatopsis sulphurea and in the pathogen Klebsiella pneumoniae. Resistance development in Klebsiella led primarily to mutations in ramR, causing increased expression of the acrAB-tolC efflux pump. Most importantly, amidochelocardin overcomes this resistance mechanism, revealing not only the improved activity profile but also superior resistance-breaking properties of this novel antibacterial compound.

Highlights

The ongoing emergence of antimicrobial resistance (AMR) and the concurrent decline in effective treatment options is a severe threat for the human population
We investigated in detail the in vitro activity of CHD and CDCHD with
We investigated in detail the in vitro activity of CHD and CDCHD with emphasis emphasis on clinically isolated uropathogens, including multidrug-resistant (MDR) strains

Summary

Introduction

The ongoing emergence of antimicrobial resistance (AMR) and the concurrent decline in effective treatment options is a severe threat for the human population. If no solutions are provided to arrest the drop in developing new effective drugs, the number of deaths due to AMR was predicted to increase up to 10 million per year in 2050 [1] This problem is accompanied by the rising evolution of multidrug-resistant (MDR) bacteria, which are described especially among hard-to-treat pathogens belonging to the ESKAPE group (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) [2,3,4]. The main source for the development of new pharmaceuticals in general, especially antibiotics, are natural products (NPs) mainly derived from plants, fungi, and bacteria [6] Among the latter, actinobacteria, in particular Streptomyces spp., represent the most relevant producers of known antibacterial NPs [7,8]. Chemical and biotechnological approaches such as semisynthesis or genetic engineering, respectively, are applied to modify such molecules, aiming to improve their pharmaceutical properties, antibacterial spectra, and efficacies [14]

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