Boosting succinylation-dependent LPS biosynthesis to overcome colistin resistance

Abstract Antibiotic resistance has become a global crisis that threatens human health and sustainable agriculture. Polymyxins, a type of cationic polypeptide antibiotics, represents one of the last lines of defense against pan-drug resistant Gram-negative pathogens. However, this antibiotic is challenged by the emergence of resistance, especially by mobilized colistin determinants (mcr-1). Overcoming polymyxin resistance is necessary to revive this antibiotic in regular therapy. Here, we present a metabolite-enabled approach to resensitize polymyxin-resistant bacteria to colistin. By applying functional metabolomics, we find that mcr-1represses the pyruvate cycle, where succinate is the crucial biomarker. Exogenous succinate reverses polymyxin resistance for both of mcr-1-positive and mcr-1-negative polymyxin-resistant bacteria isolated from animal husbandry and medical settings. This effect is confirmed in vivo by mouse and fish infection models. Furthermore, succinate increases LPS biosynthesis by promoting succinylation of transcription factors, CpxR and PdhR. The increased LPS biosynthesis in turn reduces the portion of LPS modified by mcr-1, restores surface charge and enhances colistin binding. α-ketoglutarate and metoprolol succinate, a prescribed drug, also boosts succinylation to reverse polymyxin resistance. Thus, our study presents a succinylation-based approach to reverse polymyxin resistance and reveals a previously unrecognized post-translational modification on the control of LPS biogenesis.