Structure–function correlates of fibrinogen binding by Acinetobacter adhesins critical in catheter-associated urinary tract infections

Abstract

Multidrug-resistant Acinetobacter baumannii infections are an urgent clinical problem and can cause difficult-to-treat nosocomial infections. During such infections, like catheter-associated urinary tract infections (CAUTI), A. baumannii rely on adhesive, extracellular fibers, called chaperone-usher pathway (CUP) pili for critical binding interactions. The A. baumannii uropathogenic strain, UPAB1, and the pan-European subclone II isolate, ACICU, use the CUP pili Abp1 and Abp2 (previously termed Cup and Prp, respectively) in tandem to establish CAUTIs, specifically to facilitate bacterial adherence and biofilm formation on the implanted catheter. Abp1 and Abp2 pili are tipped with two domain tip adhesins, Abp1D and Abp2D, respectively. We discovered that both adhesins bind fibrinogen, a critical host wound response protein that is released into the bladder upon catheterization and is subsequently deposited on the catheter. The crystal structures of the Abp1D and Abp2D receptor-binding domains were determined and revealed that they both contain a large, distally oriented pocket, which mediates binding to fibrinogen and other glycoproteins. Genetic, biochemical, and biophysical studies revealed that interactions with host proteins are governed by several critical residues in and along the edge of the binding pocket, one of which regulates the structural stability of an anterior loop motif. K34, located outside of the pocket but interacting with the anterior loop, also regulates the binding affinity of the protein. This study illuminates the mechanistic basis of the critical fibrinogen-coated catheter colonization step in A. baumannii CAUTI pathogenesis.

Vaccination with Acinetobacter baumannii adhesin Abp2D provides protection against catheter-associated urinary tract infection

“…While the two adhesins share a great deal of structural similarly, the anterior loop of the binding pocket is considerably more flexible in Abp1DRBD than in Abp2DRBD. 25 Because of this flexibility Abp1DRBD can adopt either a "closed" (lower affinity) or "open" (higher affinity)…”

“…[15][16][17][18][19][20][21][22][23][24] Our recent studies of A. baumannii CAUTI pathogenesis have revealed that A. baumannii CUP adhesins are critical in catheter colonization and thus may represent promising drug targets. 8,25 When a urinary catheter is inserted into the bladder, it induces inflammation and leads to deposition of host proteins, such as fibrinogen, onto the surface of the implant. 23,24,[26][27][28] A. baumannii have evolved two CUP pili, Abp1 and Abp2, tipped with fibrinogen binding adhesins Abp1D and Abp2D respectively.…”

“…The majority of published A. baumannii genomes encode one or both of these pilus operons. 25 Both of these adhesins have been shown to bind fibrinogen and to be critical in a mouse model of CAUTI. 25 Therefore, we hypothesized that targeting the Abp1D/Abp2D adhesins with an adhesin-based vaccine, comprised of their receptor binding domains Abp1D RBD and Abp2D RBD , would prevent A. baumannii CAUTI pathogenesis.…”

Clinical Efficacy and Safety of Tigecycline Based on Therapeutic Drug Monitoring for Carbapenem- Resistant Gram Negative Bacterium Pneumonia in Intensive Care Units

“…Recently, a study found that inhibition of mitochondrial DNA translation was a potential molecular mechanism [31] . A study found that Multidrugresistant Acinetobacter baumannii can bind brinogen, through two domain tip adhesins, Abp1D and Abp2D, respectively [32] .Plasminogen bound to CipA, which mediates complement resistance of Acinetobacter baumannii, could be activated to plasmin to degradation brinogen [33] . This may explain that there were no differences in APTT and PT.…”

AllTheBacteria - all bacterial genomes assembled, available and searchable

“…It included assemblies of over 300,000 genomes which had not previously been available (the raw data only had been available). The assemblies and search indexes allowed multiple other studies of plasmids[5, 6], bacterial adaptation[7, 8, 9, 10], and compression/indexing algorithms[11, 12, 13, 14, 15]. However, there were a few limitations.…”