8spm
Crystal structure of NikA in complex Ni-AMA
Structural highlights
FunctionPublication Abstract from PubMedMicrobial Ni(2+) homeostasis underpins the virulence of several clinical pathogens. Ni(2+) is an essential cofactor in urease and [NiFe]-hydrogenases involved in colonization and persistence. Many microbes produce metallophores to sequester metals necessary for their metabolism and starve competing neighboring organisms. The fungal metallophore aspergillomarasmine A (AMA) shows narrow specificity for Zn(2+), Ni(2+), and Co(2+). Here, we show that this specificity allows AMA to block the uptake of Ni(2+) and attenuate bacterial Ni-dependent enzymes, offering a potential strategy for reducing virulence. Bacterial exposure to AMA perturbs H(2) metabolism, ureolysis, struvite crystallization, and biofilm formation and shows efficacy in a Galleria mellonella animal infection model. The inhibition of Ni-dependent enzymes was aided by Zn(2+,) which complexes with AMA and competes with the native nickelophore for the uptake of Ni(2+). Biochemical analyses demonstrated high-affinity binding of AMA-metal complexes to NikA, the periplasmic substrate-binding protein of the Ni(2+) uptake system. Structural examination of NikA in complex with Ni-AMA revealed that the coordination geometry of Ni-AMA mimics the native ligand, Ni-(L-His)(2), providing a structural basis for binding AMA-metal complexes. Structure-activity relationship studies of AMA identified regions of the molecule that improve NikA affinity and offer potential routes for further developing this compound as an anti-virulence agent. Targeting bacterial nickel transport with aspergillomarasmine A suppresses virulence-associated Ni-dependent enzymes.,Sychantha D, Chen X, Koteva K, Prehna G, Wright GD Nat Commun. 2024 May 13;15(1):4036. doi: 10.1038/s41467-024-48232-1. PMID:38740750[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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