Kupyaphores are zinc homeostatic metallophores required for colonization of Mycobacterium tuberculosis

Abstract

Significance Mycobacterium tuberculosis ( Mtb ) is the etiological agent of human tuberculosis (TB). Mtb can persist inside host macrophages by successfully adapting to intracellular conditions. Acquisition of balanced amounts of essential micronutrients is one such important process. Our studies have identified a metallophore produced on demand to restore Mtb zinc metabolic imbalance. These diacyl-diisonitrile lipopeptides, named kupyaphores, are specifically induced during infection and move in and out of cells to protect bacteria from host-mediated nutritional deprivation and intoxication. Furthermore, we identify an Mtb isonitrile hydratase homolog , expressed in low-zinc conditions, which probably facilitates zinc release from kupyaphores. Identification of this zinc acquisition strategy could provide opportunities in future to understand systemic zinc dysbiosis and associated manifestations in TB patients.