6cn7

Publication Abstract from PubMed

Aerobactin, a citryl-hydroxamate siderophore, is produced by a number of pathogenic Gram-negative bacteria to aid in iron assimilation. Interest in this well-known siderophore was reignited by recent investigations suggesting that it plays a key role in mediating the enhanced virulence of a hypervirulent pathotype of Klebsiella pneumoniae (hvKP). In contrast to classical opportunistic strains of Klebsiella pneumoniae, hvKP causes serious life-threatening infections in previously healthy individuals in the community. Multiple contemporary reports have confirmed fears that the convergence of multi-drug resistant and hvKP pathotypes has led to the evolution of a highly transmissible, drug resistant, and virulent "super bug". Despite hvKP harboring four distinct siderophore operons, knocking out production of only aerobactin led to a significant attenuation of virulence. Herein, we continue our structural and functional studies on the biosynthesis of this crucial virulence factor. In vivo heterologous production and in vitro reconstitution of aerobactin biosynthesis from hvKP was carried out, demonstrating the specificity, stereoselectivity, and kinetic throughput of the complete pathway. Additionally, we present a steady-state kinetic analysis and the X-ray crystal structure of the second aerobactin synthetase IucC, as well as describe a surface entropy reduction strategy that was employed for structure determination. Finally, we show solution X-ray scattering data that supports a unique dimeric quaternary structure for IucC. These new insights into aerobactin assembly will help inform potential antivirulence strategies and advance our understanding of siderophore biosynthesis.

Structural and functional delineation of aerobactin biosynthesis in hypervirulent Klebsiella pneumoniae.,Bailey DC, Alexander E, Rice MR, Drake EJ, Mydy LS, Aldrich CC, Gulick AM J Biol Chem. 2018 Apr 4. pii: RA118.002798. doi: 10.1074/jbc.RA118.002798. PMID:29618511^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.