Kupyaphores are counter regulatory zinc homeostatic metallophores required for Mycobacterium tuberculosis colonization

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.