The zinc metalloprotein MigC impacts cell wall biogenesis through interactions with an essential Mur ligase in Acinetobacter baumannii

Jeanette M Critchlow, Joseph S Rocchio, Melanie C McKell, Courtney J Campbell, Juan P Barraza, Evan S Krystofiak, Erin R Green, Tae Akizuki, Walter J Chazin, Michael S VanNieuwenhze, Timothy L Stemmler, David P Giedroc and Eric P Skaar

PLOS Pathogens, 2025, vol. 21, issue 6, 1-24

Abstract: To colonize and survive in the host, bacterial pathogens like Acinetobacter baumannii must acquire zinc (Zn). To maintain Zn homeostasis, A. baumannii synthesizes proteins of the COG0523 family which are predicted to chaperone Zn to metalloproteins. Bioinformatic tools identified A. baumannii A1S_0934 as a COG0523 protein, and yeast two-hybrid screening revealed that MurD, an essential muramyl ligase, interacts with A1S_0934. As such, we have named A1S_0934 MurD interacting GTPase COG0523 (MigC). Here we show that MigC is a GTPase whose activity is stimulated upon Zn coordination to a characteristic CxCC (C = Cys; x = Leu/Ile/Met) motif to form a S3(N/O) complex. MigC-deficient strains (ΔmigC) display sensitivity to Zn depletion and exhibit altered cell wall architecture in vitro. Biochemical and functional assays confirm the MigC-MurD interaction, which inhibits the catalytic activity of MurD. CRISPRi knockdowns of murD reduce A. baumannii fitness and increase filamentation during Zn depletion, a phenotype reversed in ΔmigC strains, suggesting that MigC also inhibits MurD activity in cells. ΔmigC cells are elongated and sensitized to ceftriaxone, a cephalosporin antibiotic, consistent with decreased cell wall integrity. The ΔmigC strain has reduced ability to colonize in a murine model of pneumonia highlighting the importance of the MigC-MurD interaction during A. baumannii infection. Together these data suggest that MigC impacts cell wall biogenesis, in part through interactions with MurD, emphasizing the importance of MigC and MurD to the survival and pathogenicity of A. baumannii and expanding the potential functions of the COG0523 family of enzymes.Author summary: P-loop GTPase proteins of the COG0523 family are linked to adaptive growth during Zn deficiency. Here we demonstrate that A1S_0934, designated as MurD interacting GTPase COG0523 (MigC), modulates cell wall biogenesis and integrity through interactions that reduce the activity of MurD, an essential enzyme in the formation of peptidoglycan. Identification of MigC as a COG0523 protein and unveiling MurD as a binding partner of MigC underscores the importance of COG0523 proteins in bacterial physiology. Elucidating these interactions offers crucial insights into potential therapeutic strategies against multidrug-resistant A. baumannii, specifically by targeting essential cell wall enzymes such as MurD. These findings establish the potential of MigC as a novel drug target to disrupt vital pathways in peptidoglycan biosynthesis.

Date: 2025
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Persistent link: https://EconPapers.repec.org/RePEc:plo:ppat00:1013209

DOI: 10.1371/journal.ppat.1013209

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