Elsevier

Microbial Pathogenesis

Volume 77, December 2014, Pages 105-112
Microbial Pathogenesis

Review
Sortase A: An ideal target for anti-virulence drug development

https://doi.org/10.1016/j.micpath.2014.10.007Get rights and content

Highlights

  • Antibiotic-resistance of Gram-positive pathogens is a major worldwide health problem.

  • Anti-virulence drugs target the virulence of pathogens without killing or inhibiting the growth of microorganisms.

  • Anti-virulence drugs have a limited selective pressure to promote the rise in antibiotic-resistance strains.

  • The SrtA is an attractive target to design new anti-virulence agents.

Abstract

Sortase A is a membrane enzyme responsible for the anchoring of surface-exposed proteins to the cell wall envelope of Gram-positive bacteria. As a well-studied member of the sortase subfamily catalysing the cell wall anchoring of important virulence factors to the surface of staphylococci, enterococci and streptococci, sortase A plays a critical role in Gram-positive bacterial pathogenesis. It is thus considered a promising target for the development of new anti-infective drugs that aim to interfere with important Gram-positive virulence mechanisms, such as adhesion to host tissues, evasion of host defences, and biofilm formation. The additional properties of sortase A as an enzyme that is not required for Gram-positive bacterial growth or viability and is conveniently located on the cell membrane making it more accessible to inhibitor targeting, constitute additional reasons reinforcing the view that sortase A is an ideal target for anti-virulence drug development. Many inhibitors of sortase A have been identified to date using high-throughput or in silico screening of compound libraries (synthetic or natural), and while many have proved useful tools for probing the action model of the enzyme, several are also promising candidates for the development into potent inhibitors. This review is focused on the most promising sortase A inhibitor compounds that are currently in development as leads towards a new class of anti-infective drugs that are urgently needed to help combat the alarming increase in antimicrobial resistance.

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

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