Effect of membrane composition on interaction and permeation of a mycobacterial siderophore

Abstract

1Iron acquisition is a crucial determinant of Mycobacterium tuberculosis (Mtb) survival and pathogenesis, as the bacterium must scavenge iron from the host environment during infection. To achieve this, Mtb synthesizes two structurally distinct siderophores, mycobactin (MBT) and carboxymycobactin (cMBT), efficiently chelate iron and facilitate its uptake. While MBT remains embedded in the membrane due to its hydrophobicity, cMBT is secreted to scavenge extracellular iron. Despite their biological importance, the dynamics of siderophore-membrane interactions remain poorly understood. In this study, we employ coarse-grained molecular dynamics simulations to investigate the spontaneous flip-flop of iron-bound MBT (Fe-MBT) across the mycobacterial membrane. Our results reveal that Fe-MBT flip-flop occurs on a significantly slower timescale compared to generic bacterial lipids, with rates nearly an order of magnitude lower. The lipid composition of the membrane plays a critical role in modulating this process, with mycobacterial membranes exhibiting a higher degree of lipid order and reduced Fe-MBT mobility compared to generic bacterial membranes. Furthermore, we show that flip-flop transitions are relatively fast, occurring within 100 ns and, in some cases, on the order of a few nanoseconds. Our findings contribute to a mechanistic understanding of siderophore dynamics in Mtb membranes and provide a foundation for future studies on iron acquisition and potential drug targeting strategies.