Nature 561, 189–194 (2018)

Arylomycins are macrocyclic lipopeptides that have shown promise as antibiotics against Gram-positive bacteria by targeting the active site of a signal peptidase (SPase) on the cell surface. However, these natural products have limited activity against Gram-negative bacteria owing to difficulty penetrating the outer-membrane permeability barrier. Smith et al. identified an arylomycin analog, G0775, which is 500-fold more potent than the original arylomycin against Gram-negative members of the ESKAPE pathogen group of bacteria, considered the most likely species to lead to untreatable multidrug-resistant (MDR) infections. G0775 remains potent against dozens of clinical isolates of ESKAPE pathogens, including an MDR isolate of Klebsiella pneumoniae that is resistant to 13 classes of antibiotics, and is efficacious in multiple murine infection models. The authors detected a low frequency of mutations in the Gram-negative SPase LepB that resulted in resistance to G0775, suggesting this protein as its target. Indeed, structural analysis showed that resistance mutations mapped to G0775-binding residues on LepB and revealed a covalent mechanism of inhibition. Finally, G0775 seems to enter Escherichia coli by a self-promoted uptake that is enhanced by its positive charge, defining a unique mechanism of antibiotic entry and previously undrugged target in Gram-negative bacteria.

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Nature