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Published on: September 7, 2022
Sortase as a target of anti-infective therapy
Anthony W Maresso1, Olaf Schneewind
1Department of Microbiology, University of Chicago, Chicago, IL 60637, USA.
Abstract:
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.
Insights
Antibiotic-resistant bacteria, or "superbugs," pose a significant threat. Targeting sortase enzymes, crucial for bacterial cell wall assembly, offers a promising new avenue for anti-infective therapies.
Area of Science:
- Microbiology
- Biochemistry
- Drug Discovery
Background:
- Antibiotic resistance in pathogenic bacteria is a growing global health crisis.
- There is a critical need for novel therapeutic targets and antibiotics in the drug discovery pipeline.
- Sortase enzymes are essential for anchoring surface proteins and pili in Gram-positive bacteria, playing a key role in virulence.
Purpose of the Study:
- To review the catalytic mechanisms of sortase enzymes.
- To discuss the function of sortase-anchored surface proteins in bacterial pathogenesis.
- To explore the potential of inhibiting sortase-mediated anchoring as an anti-infective strategy.
Main Methods:
- Review of existing literature on sortase biochemistry and function.
- Analysis of the role of surface protein assembly in bacterial infections.
- Evaluation of strategies for inhibiting sortase activity.
Main Results:
- Sortase enzymes cleave surface protein precursors and facilitate their covalent attachment to the cell wall or other proteins.
- Sortase substrates include adhesins, internalins, and immune evasion factors essential for pathogen survival and infection.
- Inhibiting sortase-mediated anchoring disrupts the function of critical virulence factors.
Conclusions:
- Sortase-catalyzed protein anchoring is a validated and essential process for Gram-positive bacterial pathogens.
- Inhibition of sortase activity presents a promising therapeutic strategy to combat antibiotic-resistant bacteria.
- Targeting sortase offers a novel approach to developing new anti-infective agents.
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