Identification of potential antivirulence agents by substitution-oriented screening for inhibitors of Streptococcus pyogenes sortase A

Wójcik, Magdalena; Eleftheriadis, Nikolaos; Zwinderman, Martijn R. H.; Dömling, Alexander; Boersma, Ykelien L.

doi:10.1016/j.ejmech.2018.10.027

Cited by 9 publications

(11 citation statements)

References 27 publications

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“…Production and purification of proteins used in this study were performed as described previously 19 . Briefly, competent E coli BL21(DE3) cells were transformed with plasmids encoding SpSrtA WT and loop mutants.…”

Section: Methodsmentioning

confidence: 99%

Engineering the specificity of Streptococcus pyogenes sortase A by loop grafting

et al. 2020

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Sortases are a group of enzymes displayed on the cell-wall of Gram-positive bacteria. They are responsible for the attachment of virulence factors onto the peptidoglycan in a transpeptidation reaction through recognition of a pentapeptide substrate. Most housekeeping sortases recognize one specific pentapeptide motif; however, Streptococcus pyogenes sortase A (SpSrtA WT) recognizes LPETG, LPETA and LPKLG motifs. Here, we examined SpSrtA's flexible substrate specificity by investigating the role of the β7/β8 loop in determining substrate specificity. We exchanged the β7/β8 loop in SpSrtA with corresponding β7/β8 loops from Staphylococcus aureus (SaSrtA WT) and Bacillus anthracis (BaSrtA WT). While the BaSrtA-derived variant showed no enzymatic activity toward either LPETG or LPETA substrates, the activity of the SaSrtAderived mutant toward the LPETA substrate was completely abolished. Instead, the mutant had an improved activity toward LPETG, the preferred substrate of

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Section: Methodsmentioning

confidence: 99%

Engineering the specificity of Streptococcus pyogenes sortase A by loop grafting

et al. 2020

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“…The compound is structurally similar to the 3-indoleglyoxylic acid derivatives, but it had no significant effect on Sa-SrtA∆N59. The importance of the morpholino moiety for the inhibition of Sp-SrtA was demonstrated by docking studies and by the lack of effect of the corresponding piperidine derivative [ 72 ].…”

Section: Sortase a Inhibitorsmentioning

confidence: 99%

Targeting Bacterial Sortases in Search of Anti-virulence Therapies with Low Risk of Resistance Development

et al. 2021

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Increasingly ineffective antibiotics and rapid spread of multi- and pan-resistant bacteria represent a global health threat; hence, the need of developing new antimicrobial medicines. A first step in this direction is identifying new molecular targets, such as virulence factors. Sortase A represents a virulence factor essential for the pathogenesis of Gram-positive pathogens, some of which have a high risk for human health. We present here an exhaustive collection of sortases inhibitors grouped by relevant chemical features: vinyl sulfones, 3-aryl acrylic acids and derivatives, flavonoids, naphtoquinones, anthraquinones, indoles, pyrrolomycins, isoquinoline derivatives, aryl β-aminoethyl ketones, pyrazolethiones, pyridazinones, benzisothiazolinones, 2-phenyl-benzoxazole and 2-phenyl-benzofuran derivatives, thiadiazoles, triazolothiadiazoles, 2-(2-phenylhydrazinylidene)alkanoic acids, and 1,2,4-thiadiazolidine-3,5-dione. This review focuses on highlighting their structure–activity relationships, using the half maximal inhibitory concentration (IC50), when available, as an indicator of each compound effect on a specific sortase. The information herein is useful for acquiring knowledge on diverse natural and synthetic sortases inhibitors scaffolds and for understanding the way their structural variations impact IC50. It will hopefully be the inspiration for designing novel effective and safe sortase inhibitors in order to create new anti-infective compounds and to help overcoming the current worldwide antibiotic shortage.

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“…Those are not in the scope of this review. For example, inhibitors of sortase A may indirectly influence virulence by interfering with the attachment mediated by surface proteins and thereby being important for the epidemiology [ 37 ]. Inhibitors or inducers of streptococcal quorum sensing systems may also influence the GAS colonization status, either directly or indirectly through action on bacterial competitors in the throat or on the skin [ 38 , 39 ].…”

Section: Epidemiology Clinics Therapy and Preventionmentioning

confidence: 99%

Streptococcus pyogenes (“Group A Streptococcus”), a Highly Adapted Human Pathogen—Potential Implications of Its Virulence Regulation for Epidemiology and Disease Management

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Lütticken²

2021

Pathogens

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Streptococcus pyogenes (group A streptococci; GAS) is an exclusively human pathogen. It causes a variety of suppurative and non-suppurative diseases in people of all ages worldwide. Not all can be successfully treated with antibiotics. A licensed vaccine, in spite of its global importance, is not yet available. GAS express an arsenal of virulence factors responsible for pathological immune reactions. The transcription of all these virulence factors is under the control of three types of virulence-related regulators: (i) two-component systems (TCS), (ii) stand-alone regulators, and (iii) non-coding RNAs. This review summarizes major TCS and stand-alone transcriptional regulatory systems, which are directly associated with virulence control. It is suggested that this treasure of knowledge on the genetics of virulence regulation should be better harnessed for new therapies and prevention methods for GAS infections, thereby changing its global epidemiology for the better.

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Identification of potential antivirulence agents by substitution-oriented screening for inhibitors of Streptococcus pyogenes sortase A

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Cited by 9 publications

References 27 publications

Engineering the specificity of Streptococcus pyogenes sortase A by loop grafting

Engineering the specificity of Streptococcus pyogenes sortase A by loop grafting

Targeting Bacterial Sortases in Search of Anti-virulence Therapies with Low Risk of Resistance Development

Streptococcus pyogenes (“Group A Streptococcus”), a Highly Adapted Human Pathogen—Potential Implications of Its Virulence Regulation for Epidemiology and Disease Management

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