by manipulating bacterial labile iron pool, where ferrous iron accumulates at the expense of ferric and total iron. This change in iron abundance leads to inactivation of the PmrA/B two-component system and subsequent PmrA/B-dependent lipopolysaccharide modifications, finally promoting colistin to bind and destabilize the bacterial membrane. Meanwhile, increased ferrous iron, in response to colistin-induced ROS, results in ferroptotic-like damage, which generates lethal reactive electrophilic species to deteriorate the essential cellular constituents. These data underscore an exploitable link between iron homeostasis and colistin susceptibility, as both primary and secondary actions of colistin respond to the shifts in cellular labile iron. To sum, this study offers a translationally viable regimen of baicalein-colistin combination against Gram-negative pathogen infection and reveals the cellular labile iron as a generally applicable target for developing next-generation colistin adjuvants.
Zhang et al. (Tue,) studied this question.