Abstract
Proteus mirabilis, a Gram-negative uropathogen, is a major causative agent in catheter-associated urinary tract infections (CAUTI). Mannose-resistant Proteus-like fimbriae (MR/P) are crucially important for P. mirabilis infectivity and are required for biofilm formation and auto-aggregation, as well as for bladder and kidney colonization. Here, the X-ray crystal structure of the MR/P tip adhesin, MrpH, is reported. The structure has a fold not previously described and contains a transition metal center with Zn2+ coordinated by three conserved histidine residues and a ligand. Using biofilm assays, chelation, metal complementation, and site-directed mutagenesis of the three histidines, we show that an intact metal binding site occupied by zinc is essential for MR/P fimbria-mediated biofilm formation, and furthermore, that P. mirabilis biofilm formation is reversible in a zinc-dependent manner. Zinc is also required for MR/P-dependent agglutination of erythrocytes, and mutation of the metal binding site renders P. mirabilis unfit in a mouse model of UTI. The studies presented here provide important clues as to the mechanism of MR/P-mediated biofilm formation and serve as a starting point for identifying the physiological MR/P fimbrial receptor.
Highlights
The urinary tract is a primary target for bacterial infections [1]
Many bacteria use fimbriae to adhere to surfaces, and this function is often essential for pathogens to gain a foothold in the host
This species is known for causing catheter-associated urinary tract infections, in which it forms damaging urinary stones and crystalline biofilms that can block the flow of urine through indwelling catheters
Summary
The urinary tract is a primary target for bacterial infections [1]. Urinary tract infections (UTIs) are categorized as uncomplicated or complicated. Uncomplicated UTIs occur in individuals that are otherwise healthy, with uropathogenic Escherichia coli (UPEC) as the main causative agent [2,3]. Complicated UTIs affect patients with underlying difficulties such as indwelling catheters or anatomic obstructions. Catheter-associated UTIs (CAUTI) are one of the most common healthcare-associated infections [4,5]. A Gram-negative member of the Enterobacterales bacterial order famous for its ability to swarm over surfaces, including urinary catheters, is a major causative agent in CAUTI [6,7,8]
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