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Published online before print March 5, 2008

0031-6997/08/6001-128-141$7.00
Pharmacol Rev 60:128-141, 2008

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Sortase as a Target of Anti-Infective Therapy

Anthony W. Maresso and Olaf Schneewind

Department of Microbiology, University of Chicago, Chicago, Illinois

Abstract
I. Targeting Virulence Factors as a Therapy for Bacterial Infections
II. Staphylococcus aureus
    A. Clinical Disease and Epidemiology
    B. Staphylococcal Virulence Genes
    C. The Staphylococcal Cell Wall Envelope
    D. Surface Protein
III. Sortase
    A. Sortase-Catalyzed Transpeptidation
    B. Sortase Structure and Catalysis
    C. The Pathway of Surface Protein Anchoring
    D. Sortases, Surface Proteins, and the Pathogenesis of Microbial Infections
    E. Iron Acquisition
    F. Sortase and Pili
    G. Sortase and Sporulation
IV. The Inhibition of Sortase
    A. Early Observations
    B. Natural Products
    C. Rational Design
    D. High-Throughput Screen
V. On the Development of Sortase Inhibitors
    A. Assay Design
    B. In Vivo Evaluation of Sortase Inhibitors
VI. Summary
The rise in antibiotic-resistant bacteria is a major concern, in particular because it includes many different species of pathogenic microbes. These "superbugs" are further characterized by high levels of virulence and disease-associated mortality. There seems to be few new antibiotics in the drug discovery pipeline; recent work has sought to define and validate new drug targets. The assembly of surface proteins and pili in the cell wall envelope of Gram-positive bacteria is catalyzed by sortase. Sortase cleaves a conserved C-terminal sequence of these polypeptides to generate an acyl-enzyme intermediate. The acyl-enzyme is next resolved by nucleophilic attack by the amino groups within cell wall cross-bridges or pilin proteins, thereby covalently attaching the polypeptides to the cell wall or the next pilin subunit. Sortase substrates function as adhesins, internalins, blood clotting and immune evasion factors, and transporters for nutrients across the microbial cell wall envelope; without them, most pathogens cannot sustain an infection. Here we review what is known about sortase catalysis and surface protein function, how surface protein anchoring can be inhibited, and what prospects such inhibition may have for anti-infective therapy.

Address correspondence to: Dr. Olaf Schneewind, Department of Microbiology, University of Chicago, CLSC Room 601, 920 E. 58th Street, Chicago, IL 60637. E-mail: oschnee{at}bsd.uchicago.edu




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P. R. Race, M. L. Bentley, J. A. Melvin, A. Crow, R. K. Hughes, W. D. Smith, R. B. Sessions, M. A. Kehoe, D. G. McCafferty, and M. J. Banfield
Crystal Structure of Streptococcus pyogenes Sortase A: IMPLICATIONS FOR SORTASE MECHANISM
J. Biol. Chem., March 13, 2009; 284(11): 6924 - 6933.
[Abstract] [Full Text] [PDF]


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