Discovery of a Siderophore Export System Essential for Virulence of Mycobacterium tuberculosis

• DOI: 10.1371/journal.ppat.1003120
• Publication Date: 2013-01-31T21:53:59Z
• Authors: Ryan M. Wells; Christopher M. Jones; Zhaoyong Xi; Alexander Speer; Olga Danilchanka; Kathryn S. Doornbos; Peibei Sun; Fangming Wu; Changlin Tian; Michael Niederweis
• Keywords: Efflux

Iron is an essential nutrient for most bacterial pathogens, but restricted by the host immune system. Mycobacterium tuberculosis (Mtb) utilizes two classes of small molecules, mycobactins and carboxymycobactins, to capture iron from human host. Here, we show that Mtb mutant lacking mmpS4 mmpS5 genes did not grow under low conditions. A cytoplasmic reporter indicated double experienced starvation even high-iron Loss change uptake carboxymycobactin Mtb. Thin layer chromatography showed ΔmmpS4/S5 was strongly impaired in biosynthesis secretion siderophores. Pull-down experiments with purified proteins demonstrated MmpS4 binds a periplasmic loop associated transporter protein MmpL4. This interaction corroborated genetic experiments. While MmpS5 interacted only MmpL5, both MmpL4 MmpL5. These results identified MmpS4/MmpL4 MmpS5/MmpL5 as siderophore export systems revealed MmpL transport molecules other than lipids. resemble adapter tripartite efflux pumps Gram-negative bacteria, however, they are required also efficient synthesis. Membrane association MbtG suggests link between synthesis transport. The structure soluble domain (residues 52-140) solved NMR indicates mycobacterial MmpS constitute novel class accessory proteins. burden mmpS4/S5 deletion mouse lungs lower 10,000-fold none infected mice died within 180 days compared wild-type strongest attenuation observed so far mutants involved utilization. In conclusion, this study first components which virulence