The Myxobacterial Antibiotic Myxovalargin: Biosynthesis, Structural Revision, Total Synthesis, and Molecular Characterization of Ribosomal Inhibition

Abstract

Resistance of bacterial pathogens against antibiotics is declared by WHO as a major global health threat. As novel antibacterial agents are urgently needed, we re-assessed the broad-spectrum myxobacterial antibiotic myxovalargin and found it to be extremely potent against Mycobacterium tuberculosis. To ensure compound supply for further development, we studied myxovalargin biosynthesis in detail enabling production via fermentation of a native producer. Feeding experiments as well as functional genomics analysis suggested a structural revision, which was eventually corroborated by the development of a concise total synthesis. The ribosome was identified as the molecular target based on resistant mutant sequencing, and a cryo-EM structure revealed that myxovalargin binds within and completely occludes the exit tunnel, consistent with a mode of action to arrest translation during a late stage of translation initiation. These studies open avenues for structure-based scaffold improvement toward development as an antibacterial agent.

Dehydroamino acid residues in bioactive natural products

“…17 NRPs possess other dhAA residues with great structural diversity, for example, Z-dehydrotryptophan (Z-DTrp) in telomycin 27 found in a Streptomyces strain; 73 Z-dehydroarginine (Z-DArg) in odilorhabdin 28 isolated from the nematode-symbiotic bacterium Xenorhabdus nematophila; 74,75 Z-b-ureidodehydroalanine in viomycin 29 (ref. 76) and aziridino[1,2-a]pyrrolidine in antitumour antibiotic azinomycins 30, produced by the culture broth of Streptomyces species; 77 O-aryl-N-methyl-Dtyrosine and E-2-amino-3-hydroxymethyl-4,5-epoxy-a,b-dehydropentanoic acid residues in dityromycin 31; 78 DVal in myxovalargin A 32 from Myxococcus fulvus strain Mx f65; 79 and an N-methyl-Z-dehydrophenylalanine residue (N-methyl-Z-DPhe) in tentoxin 33, a phytotoxic metabolite of the pathogenic fungus Alternaria tenuis 80 (Fig. 10).…”

Recent advances in discovery and biosynthesis of natural products from myxobacteria: an overview from 2017 to 2023

“…This mode-of-action study sets the stage for future structure-based structural improvement to overcome the disadvantages of myxovalargins, including compound availability and narrow therapeutic index. 138 Surup and co-workers discovered two cyclic depsipeptides termed crocadepsins A (74) and B (75) from the myxobacterium Chondromyces crocatus Cm c5 by integrating genome mining and comparative metabolomics approaches. 139 These compounds feature cinnamoyl, dehydrobutyrine, chlorination, b-hydroxy-g-amino acid residue, and 3-methyl ornithine moieties, respectively.…”

“…135–137 Very recently, Koller and co-workers revised the l -configuration at the Val 10 residue that was previously misassigned the d stereochemistry. 138 They reassessed the antimicrobial spectrum of 73 and found that it exhibited potent antitubercular activity with an MIC of 0.2 μg mL −1 in addition to other pathogens. Compound 73 demonstrated in vivo efficacy in a mouse model of acute M. tuberculosis infection and displayed good pharmacokinetic properties with no adverse effects, opening up a potential therapeutic window for application.…”

“…This mode-of-action study sets the stage for future structure-based structural improvement to overcome the disadvantages of myxovalargins, including compound availability and narrow therapeutic index. 138 …”

New myxobacteria of the Myxococcaceae clade produce angiolams with antiparasitic activities

“…This plethora of natural products holds the promise of hidden bioactivities against often under-screened pathogens. Considering myxobacterial natural products, this is displayed by the recent findings of chondramides active against SARS-CoV-2 ( 14 ), the antitubercular properties of myxovalargin ( 15 ), or the potent anti-filarial activity of corallopyronin A through the inhibition of Wolbachia endosymbionts ( 16 ). Moreover, evaluation of the biosynthesis can be used to improve production titers in the heterologous expression of a natural product, as displayed for corallopyronin A ( 17 ), or to heterologously produce improved derivatives of a natural product family, as displayed for disorazoles ( 18 ).…”