Structure of VanH from Acinetobacter baumannii reveals domain dynamics and provides a platform for Anti-resistance drug design.

Acinetobacter baumannii is an opportunistic pathogen increasingly associated with multidrug-resistant infections. Although vancomycin resistance is uncommon in Gram-negative bacteria, the emergence of resistant A. baumannii strains underscores the importance of elucidating the underlying mechanisms. VanH is a critical enzyme that catalyzes the NAD(P)H-dependent reduction of pyruvate to d-lactate, thereby enabling cell wall remodeling required for vancomycin resistance. Here, we report the crystal structure of VanH from A. baumannii, which forms a homodimer and exhibits a two-domain architecture comprising a nucleotide-binding domain (NBD) and a substrate-binding domain (SBD). These domains are connected by a flexible linker that permits substantial interdomain movement, likely facilitating catalytic activity. Leveraging this structural information, we performed in silico virtual screening and identified four chemical compounds predicted to interact with the interdomain pocket of VanH. Collectively, these findings provide critical structural insights into VanH and establish a framework for the rational design of inhibitors to combat vancomycin resistance.