Mycobacterium tuberculosis (Mtb) endures a combination of metal scarcity and toxicity throughout the human infection cycle, contributing to complex clinical manifestations. Pathogens counteract this paradoxical dysmetallostasis by producing specialized metal trafficking systems. Capture of extracellular metal by siderophores is a widely accepted mode of iron acquisition, and Mtb iron-chelating siderophores, mycobactin, have been known since 1965. Currently, it is not known whether Mtb produces zinc scavenging molecules. Here, we characterize low-molecular-weight zinc-binding compounds secreted and imported by Mtb for zinc acquisition. These molecules, termed kupyaphores, are produced by a 10.8 kbp biosynthetic cluster and consists of a dipeptide core of ornithine and phenylalaninol, where amino groups are acylated with isonitrile-containing fatty acyl chains. Kupyaphores are stringently regulated and support Mtb survival under both nutritional deprivation and intoxication conditions. A kupyaphore-deficient Mtb strain is unable to mobilize sufficient zinc and shows reduced fitness upon infection. We observed early induction of kupyaphores in Mtb-infected mice lungs after infection, and these metabolites disappeared after 2 wk. Furthermore, we identify an Mtb-encoded isonitrile hydratase, which can possibly mediate intracellular zinc release through covalent modification of the isonitrile group of kupyaphores. Mtb clinical strains also produce kupyaphores during early passages. Our study thus uncovers a previously unknown zinc acquisition strategy of Mtb that could modulate host–pathogen interactions and disease outcome.

A competent method for the construction of highly substituted furans catalyzed by Pd­(II) and Cu­(II) chloride has been developed. The method provides easy access to di-, tri-, and tetrasubstituted furans from corresponding diols with relatively mild conditions in a unified strategy. The developed method has been successfully tested with more than 25 substrates, which resulted in furans of multiple substitution patterns with up to 84% isolated yields.

Tuberculosis (TB) patients suffer from progressive and debilitating loss of muscle mass and function, referred to as cachexia. Though a multifactorial condition, cachexia in cancer is promoted by systemic zinc redistribution and accumulation in muscles. Clinical studies with TB patients indeed show zinc dyshomeostasis. We therefore set out to understand mechanisms by which Mycobacterium tuberculosis (Mtb) govern zinc metallostasis at the host-pathogen interface. Here, we report a novel zinc metallophore from Mtb that restores zinc metabolic imbalance. These diisonitrile lipopeptides, named kupyaphores are transiently induced early-on during macrophage infection and also in infected mice lungs. Kupyaphores protects bacteria from host-mediated nutritional deprivation and intoxication. Kupyaphore Mtb mutant strain cannot mobilize zinc and shows reduced fitness in mice. Further, we characterize Mtb encoded isonitrile hydratase that could mediate intracellular zinc release through covalent modification of kupyaphores. Our studies could provide a molecular link between TB-induced altered zinc homeostasis and associated cachexia.