FIG 5.

Redox-dependent anti-infective mechanisms of action for cysteamine/cystamine. (Step 1) Cysteamine can be supplied therapeutically or produced endogenously through the action of vanin-1 pantetheinase. (Steps 2 and 3) Cysteamine itself does not pass the bacterial cytoplasmic membranes of rapidly dividing cells (step 2) but is reported to have impacts upon host immunity to infection and autophagy (step 3). (Steps 4 and 5) Cysteamine can react (reversibly) with susceptible cysteine residues in a process termed cysteaminylation (step 4), and we demonstrated that it can form adducts with reactive nitrogen species, possibly forming S-nitrosocysteamine in mildly acidic environments (step 5). (Steps 6 and 7) Cysteamine readily forms the disulfide cystamine (and water) in the presence of oxygen (step 6) in a temperature-dependent manner and at millimolar concentrations rapidly generates ROS in the presence of transition metal ions (step 7). (Steps 8 and 9) Cystamine itself may interact with unknown periplasmic targets in Gram-negative cells and can enter the bacterial cell (step 8) via an unknown mechanism, where it generates ROS and interacts with susceptible intracellular targets, leading to dysregulation of small thiol pools and metabolism (step 9), disrupting pigment production or export. (Step 10) Reduced thiols, probably including cysteamine, are exported via an unknown mechanism.