ReviewSortase A: An ideal target for anti-virulence drug development
Introduction
Gram-positive bacteria are a significant cause of nosocomial and community-acquired infections associated with diseases of high morbidity and mortality. Moreover, antibiotic resistance of important Gram-positive pathogens, such as Staphylococcus aureus, Streptococcus pneumoniae and Enterococcus faecalis is one of the major worldwide health problems [1].
Recent increasing antimicrobial resistance combined with a prominent lack of pharmaceutical investment into the development of new antibiotics, has stimulated research into alternative strategies to conventional antibiotics for counteracting bacterial pathogens [2]. Over the last decade, many studies have focused on agents that target the virulence of important pathogens without killing or inhibiting their growth therefore imposing limited selective pressure to promote the development and spread of resistance mechanisms [3].
The role of sortase enzymes in the virulence of many Gram-positive pathogens, including staphylococci, streptococci, enterococci and Listeria monocytogenes, is well established, making sortases good targets for the design of new agents that can interfere with pathogenesis [4]. A phylogenetic analyses of 61 sortase genes encoded in 22 Gram-positive bacterial genomes has grouped sortases into four different classes (A to D) [5]. Sortase A (SrtA) is present in almost all strains belonging to low GC% Gram-positive species and plays an important role in different stages of the pathogenic process in many Gram-positive bacteria [6].
The scope of this review is to describe state of the art approaches in screening for and identifying novel compounds (chemically synthesized or obtained from natural sources) that act as potent Sortase A inhibitors, as well as the research efforts into their development as anti-virulence drugs for the alternative or complementary treatment of infectious diseases in the near future.
Section snippets
Sortase A is an ideal antivirulence target
Sortase A (SrtA) is a membrane-bound cysteine transpeptidase that is responsible for catalysing the covalent anchoring of surface proteins to the Gram-positive bacterial cell wall. In S. aureus, these surface proteins are known as microbial surface components recognizing adhesive matrix molecules (MSCRAMMs) and play significant roles in bacterial adhesion and invasion of host tissues, biofilm formation, and immune evasion by inhibition of opsonization and phagocytosis. Thus, many MSRAMMs are
Discovery of SrtA inhibitors
The first important step in the synthesis of new derivatives of pharmacological interest is to identify a hit compound; this process can nowdays be facilitated by several different techniques. For SrtA in particular, High-Throughput Screening (HTS) of synthetic or natural compound libraries as well as virtual screening approaches have successfully used and have identified several inhibitor hits to date, most of which have been used to model the action of the enzyme, while others have provided
Synthetic small molecules
Many of the promising compound hits identified by large library high-throughput or virtual screens have been elaborated further and developed into lead candidates for antivirulence drugs targeting SrtA. Following a small molecule screen for new SrtA inhibitors, Oh et al. identified methyl(2E)-2,3-bis(4-methoxyphenyl)prop-2-enoate (Fig. 1, Compound 1) as a promising hit with an IC50 value of 231 μM and used it as a starting point for further elaboration [33]. Their activity data suggested that
Natural products
Natural products have also been shown to be active against SrtA with several classes described to date (Table 2). Early studies that screened large collections of medicinal plant extracts for sortase inhibitory activity, identified the ethyl acetate fraction from Cocculus trilobus as a potent SrtA inhibitor with an IC50 of 1.52 μg/ml [50]. The first natural compound with demonstrated sortase inhibitory activity was described by Kim et al., in 2003 and was the glucosylsterol
Peptides
Another important class of known SrtA inhibitors are the substrate-derived peptides. A first report in 2002, described the synthesis and kinetic evaluation of two promising members of this class of SrtA inhibitors [66]. Peptidyl-diazomethane and peptidyl-chloromethane analogues Cbz (benzyloxycarbonyl)- Leu-Pro-Ala-Thr-CHN2 and Cbz-Leu-Pro-Ala-Thr-CH2Cl were both shown to act as time-dependent irreversible inhibitors of recombinant sortase (SrtAΔN). The peptide inhibitor sequences mimic the
Conclusion
Several studies have confirmed the important role of SrtA in bacterial pathogenesis and its potential as a suitable target for pharmacological inhibition. In this review, we have provided a comprehensive description of the current most promising molecules from a variety of different classes (small synthetic organic compounds and natural products) that act as SrtA inhibitors and have the potential of being developed into future anti-virulence drugs based on their promising activity at the low
References (71)
Antibiotic resistance: the perfect storm
Int. J. Antimicrob. Agents
(2009)- et al.
Sorting sortases: a nomenclature proposal for the various sortases of Gram-positive bacteria
Res. Microbiol.
(2005) - et al.
The biology of Gram-positive sortase enzymes
Trends Microbiol.
(2004) - et al.
Sec-secretion and sortase-mediated anchoring of proteins in Gram-positive bacteria
Biochim. Biophys. Acta
(2014 Aug) - et al.
Sorting of protein A to the staphylococcal cell wall
Cell
(1992) - et al.
Anchoring of surface proteins to the cell wall of Staphylococcus aureus. III. Lipid II is an in vivo peptidoglycan substrate for sortase-catalyzed surface protein anchoring
J. Biol. Chem.
(2002) - et al.
The role of Streptococcus pneumoniae sortase A in colonisation and pathogenesis
Microbes Infect. Inst. Pasteur
(2006) - et al.
Crystal structure of Streptococcus pyogenes sortase A: implications for sortase mechanism
J. Biol. Chem.
(2009) - et al.
Disruption of srtA gene in Streptococcus suis results in decreased interactions with endothelial cells and extracellular matrix proteins
Vet. Microbiol.
(2008) - et al.
A simple statistical parameter for use in evaluation and validation of high throughput screening assays
J. Biomol. Screen
(1999)
Development of a high-performance liquid chromatography assay and revision of kinetic parameters for the Staphylococcus aureus sortase transpeptidase SrtA
Anal. Biochem.
Anchoring of surface proteins to the cell wall of Staphylococcus aureus. Sortase catalyzed in vitro transpeptidation reaction using LPXTG peptide and NH(2)-Gly(3) substrates
J. Biol. Chem.
Discovery and structure-activity relationship analysis of Staphylococcus aureus sortase A inhibitors
Bioorg. Med. Chem.
Activation of inhibitors by sortase triggers irreversible modification of the active site
J. Biol. Chem.
Crystal structures of Staphylococcus aureus sortase A and its substrate complex
J. Biol. Chem.
Identification of novel inhibitors of bacterial surface enzyme Staphylococcus aureus Sortase A
Bioorg. Med. Chem. Lett.
Therapeutic effect of (Z)-3-(2,5-dimethoxyphenyl)-2-(4-methoxyphenyl) acrylonitrile (DMMA) against Staphylococcus aureus infection in a murine model
Biochem. Biophys. Res. Commun.
The crystal structure of human cathepsin F and its implications for the development of novel immunomodulators
J. Mol. Biol.
Probing of the cis-5-phenyl proline scaffold as a platform for the synthesis of mechanism-based inhibitors of the Staphylococcus aureus sortase SrtA isoform
Bioorg. Med. Chem.
Characterization of a novel NADH-specific, FAD-containing, soluble reductase with ferric citrate reductase activity from maize seedlings
Arch. Biochem. Biophys.
Synthetic analogs of indole-containing natural products as inhibitors of sortase A and isocitrate lyase
Bioorg. Med. Chem. Lett.
Synthesis and structure activity relationship studies of novel Staphylococcus aureus Sortase A inhibitors
Eur. J. Med. Chem.
Curcumin reduces Streptococcus mutans biofilm formation by inhibiting sortase A activity
Arch. Oral Biol.
Bis(indole) alkaloids as sortase A inhibitors from the sponge Spongosorites sp
Bioorg. Med. Chem. Lett.
Aaptamines as sortase A inhibitors from the tropical sponge Aaptos aaptos
Bioorg. Med. Chem. Lett.
Beta-carboline alkaloids derived from the ascidian Synoicum sp
Bioorg. Med. Chem.
Sortase from Staphylococcus aureus does not contain a thiolate-imidazolium ion pair in its active site
J. Biol. Chem.
Synthesis of (2R,3S) 3-amino-4-mercapto-2-butanol, a threonine analogue for covalent inhibition of sortases
Bioorg. Med. Chem. Lett.
Inhibition of the Staphylococcus aureus sortase transpeptidase SrtA by phosphinic peptidomimetics
Bioorg. Med. Chem.
Beyond conventional antibiotics for the future treatment of methicillin-resistant Staphylococcus aureus infections: two novel alternatives
FEMS Immunol. Med. Microbiol.
Anti-virulence strategies to combat bacteria-mediated disease
Nat. Rev. Drug Discov.
Staphylococcus aureus sortase mutants defective in the display of surface proteins and in the pathogenesis of animal infections
Proc. Natl. Acad. Sci. U. S. A.
Purification and characterization of sortase, the transpeptidase that cleaves surface proteins of Staphylococcus aureus at the LPXTG motif
Proc. Natl. Acad. Sci. U. S. A.
Anchor structure of cell wall surface proteins in Listeria monocytogenes
Biochemistry (Mosc)
Proteome analysis of membrane and cell wall associated proteins from Staphylococcus aureus
J. Proteome Res.
Cited by (146)
Synthetic non-toxic anti-biofilm agents as a strategy in combating bacterial resistance
2023, European Journal of Medicinal ChemistryBiofilms: Understanding the structure and contribution towards bacterial resistance in antibiotics
2023, Medicine in MicroecologyWearable battery-free smart bandage with peptide functionalized biosensors based on MXene for bacterial wound infection detection
2023, Sensors and Actuators B: Chemical