Tideglusib and Its Analogues As Inhibitors of Staphylococcus aureus SrtA

Abstract

Sortase A (SrtA) anchors surface proteins to the cell wall envelope, and it has attracted increasing interesting as a potential antivirulence target. Several small-molecule inhibitors for SrtA have been developed, but target validation remains largely underexplored. Herein, we report a new class of SrtA inhibitors that supports antivirulence therapy through small-molecule targeting of SrtA. Tideglusib (TD), a drug candidate for myotonic dystrophy, was outstanding in high-throughput screening. A concise synthetic route quickly provided TD analogues, and the structure–activity relationships for SrtA inhibition have been established from those analogues. Several compounds largely retained the in vitro potency and exhibited a better solubility than TD. Additionally, TD attenuated virulence-related phenotypes in vitro and protected mice against lethal S. aureus USA300 bacteremia. Our study indicates that TD and its analogues could be new candidates as SrtA inhibitors with potential in the development of new antivirulence agents.

Design and Synthesis of Small Molecules as Potent Staphylococcus aureus Sortase A Inhibitors

“…Several significant small organic molecules have been designed and synthesized, as shown in Figure 2 , with promising IC 50 values. Herein, the concrete synthetic features and the analytic properties for structural identification are described in the order of diarylacrylonitriles [ 38 ], pyridazinones [ 39 ], aryl 3-acryloamides [ 40 ], dihydro-β-carboline [ 41 ], benzisothiazolinones [ 42 ], triazolothiadiazoles [ 43 ], 2-(2-phenylhydrazinylidene)alkanoates [ 44 ], 2-phenyl-benzo[ d ]oxazole-7-carboxamide [ 45 ], 2-phenyl-benzofuran-7-carboxamide [ 46 ], 2-phenylthiazoles [ 47 ], 2, 5-disubstitued thiadiazole [ 48 ], and thiadiazolidinedione [ 49 ].…”

“…In an attempt to discover innovative scaffolds for sortase A inhibitors, the S. Yang and C.-G Yang research groups employed FRET-based HTS on a library consisting of over 2400 clinical drugs and candidates [ 49 ]. Tideglusib (TD), a drug candidate for myotonic dystrophy [ 84 ], was identified as a hit structure with an IC 50 value of 5.9 μM.…”

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

“…Based on the bis(indolyl)imidazole scaffold of topsentins derivatives, a molecular docking study on drug-like structures coupled with an experimental validation assay on Sa- A screening for Sa-SrtA inhibitors on a collection of close to 2400 clinical drugs and candidates led to the identification of tideglusib (IC 50 = 0.6 µM), an irreversible non-ATP-competitive glycogen synthase kinase 3β (GSK-3β) inhibitor [92]. Interestingly, the proposed GSK-3β inhibition mechanism, even if not unequivocally demonstrated, involves the enzyme's Cys199 residue [93] and it could be similar in the SrtA case.…”

“…The substitution of the naphtyl with a 3,5-dimethylisoxazole ring retained the SrtA inhibition, coupled with a better water solubility. The treatment with tideglusib in a dose of 40 mg/kg/day of BALB/c mice infected with S. aureus USA300 improved the 10-days survival rate to 40%, as to 10% in non-treated animals [ 92 ].…”

Staphylococcal Infections: Host and Pathogenic Factors

“…This paper demonstrates that though there is no significant decrease in adherence and invasion in a human cell line, the mutant srt A exhibited a decrease in biofilm production, as well as affected the transcription of two different adhesins genes (Fbl and vWbF). Since srt A in different pathogens is considered as a therapeutic target [ 60 , 61 ], the characterization of this locus in new species is critical to understanding the pathogen.…”