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Resistance to last-resort polymyxin antibiotics, which includes colistin, is growing. These antibiotics interact with the lipid A component of lipopolysaccharide (LPS), which leads to destabilization of the Gram-negative outer membrane followed by rupture and leakage of cytoplasmic contents. Resistance to polymyxin antibiotics — such as that conferred by the mobilized colistin resistance gene, mcr-1 — is largely mediated through covalent modification of lipid A phosphates, which reduces the affinity of polymyxins for LPS. Using combination therapy to restore sensitivity to polymyxins is a promising approach to combating resistance. Here, Carfrae et al. demonstrate that the biotin synthesis inhibitor MAC13772 (which indirectly disrupts fatty acid synthesis (FAS)) and FAS inhibitors (cerulenin and triclosan) reverse colistin resistance against mcr-1-expressing Enterobacteriaceae and colistin-resistant Gram-negative clinical isolates, and prevent the development of spontaneous colistin resistance in E. coli. In mice, the combination of colistin and Debio1452-NH3 (an analogue of the FAS inhibitor, Debio1452, currently in Phase II clinical trials) was effective against systemic mcr-1-expressing hypervirulent K. pneumoniae and colistin-resistant E. coli infections. FAS inhibition likely restores colistin sensitivity through modification of membrane phospholipid composition.