YgiV promoter mutations cause resistance to cystobactamids and reduced virulence factor expression in Escherichia coli.

Antimicrobial resistance is one of the major health threats of the modern world. Thus, new structural classes of antimicrobial compounds are needed in order to overcome existing resistance. Cystobactamids represent one such new compound class that inhibit the well-established target bacterial type II topoisomerases while exhibiting superior antibacterial and resistance-breaking properties.

Improved broad-spectrum antibiotics against Gram-negative pathogens darobactin biosynthetic pathway engineering.

The development of new antibiotics is imperative to fight increasing mortality rates connected to infections caused by multidrug-resistant (MDR) bacteria. In this context, Gram-negative pathogens listed in the WHO priority list are particularly problematic. Darobactin is a ribosomally produced and post-translationally modified bicyclic heptapeptide antibiotic selectively killing Gram-negative bacteria by targeting the outer membrane protein BamA.

Synergizing the potential of bacterial genomics and metabolomics to find novel antibiotics.

Antibiotic development based on natural products has faced a long lasting decline since the 1970s, while both the speed and the extent of antimicrobial resistance (AMR) development have been severely underestimated. The discovery of antimicrobial natural products of bacterial and fungal origin featuring new chemistry and previously unknown mode of actions is increasingly challenged by rediscovery issues. Natural products that are abundantly produced by the corresponding wild type organisms often featuring strong UV signals have been extensively characterized, especially the ones produced by extensively screened microbial genera such as streptomycetes.

In vivo and in vitro reconstitution of unique key steps in cystobactamid antibiotic biosynthesis.

Cystobactamids are myxobacteria-derived topoisomerase inhibitors with potent anti-Gram-negative activity. They are formed by a non-ribosomal peptide synthetase (NRPS) and consist of tailored para-aminobenzoic acids, connected by a unique α-methoxy-L-isoasparagine or a β-methoxy-L-asparagine linker moiety. We describe the heterologous expression of the cystobactamid biosynthetic gene cluster (BGC) in Myxococcus xanthus.

Heterologous expression of the atypical tetracycline chelocardin reveals the full set of genes required for its biosynthesis.

Background: Chelocardin (CHD) exhibits a broad-spectrum antibiotic activity and showed promising results in a small phase II clinical study conducted on patients with urinary tract infections. Importantly, CHD was shown to be active also against tetracycline-resistant Gram-negative pathogens, which is gaining even more importance in today's antibiotic crisis. We have demonstrated that modifications of CHD through genetic engineering of its producer, the actinomycete Amycolatopsis sulphurea, are not only possible but yielded even more potent antibiotics than CHD itself, like 2-carboxamido-2-deacetyl-chelocardin (CD-CHD), which is currently in preclinical evaluation.

Dual-function chromogenic screening-based CRISPR/Cas9 genome editing system for actinomycetes.

Actinobacteria are one of the most important sources of pharmaceutically valuable and industrially relevant secondary metabolites. Modern genome mining reveals that the potential for secondary metabolite production of actinomycetes has been underestimated. Recently, the establishment of CRISPR/Cas9-based genetic manipulation approaches in actinomycetes opened a new era for genome engineering of this type of organism.

Genome mining reveals uncommon alkylpyrones as type III PKS products from myxobacteria.

Type III polyketide synthases (PKSs) are comparatively small homodimeric enzymes affording natural products with diverse structures and functions. While type III PKS biosynthetic pathways have been studied thoroughly in plants, their counterparts from bacteria and fungi are to date scarcely characterized. This gap is exemplified by myxobacteria from which no type III PKS-derived small molecule has previously been isolated.

Metabolic and Biosynthetic Diversity in Marine Myxobacteria.

Prior to 2005, the vast majority of characterized myxobacteria were obtained from terrestrial habitats. Since then, several species of halotolerant and even obligate marine myxobacteria have been described. Chemical analyses of extracts from these organisms have confirmed their ability to produce secondary metabolites with unique chemical scaffolds.