The rise of multidrug-resistant bacteria is cause for considerable concern and the ‘ESKAPE’ group of pathogens present the most acute risk of untreatable infections. The Gram-negative bacteria within this group — iEscherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii — are of particular concern because their dual-membrane envelope stops many drugs from reaching their targets. Despite extensive efforts, no new antibiotic active against Gram-negative bacteria has been approved in the past 50 years. In this week’s issue, Christopher Heise, Peter Smith and their colleagues present the chemical optimization of the arylomycin class of natural products into a potent, broad-spectrum drug that is active against clinical isolates of Gram-negative bacteria in vitro and in multiple in vivo infection models. The team believes this should pave the way for optimized arylomycin analogues to become much-needed new drugs for multidrug-resistant Gram-negative infections.