Розробка нових низькомолекулярних інгібіторів сортази А Staphylococcus aureus за допомогою гібридного віртуального скринінгу

Нещодавно, була опублікована стаття, присвячена розробці інгібіторів сортази А Staphylococcus aureus за допомогою методів молекулярного докінгу та фармакофорного скринінгу .

Abstract:

Staphylococcus aureus is one of the most dangerous pathogens commonly associated with high levels of morbidity and mortality. Sortase A is considered as a promising molecular target for the development of antistaphylococcal agents. Using hybrid virtual screening approach and FRET analysis, we have identified five compounds able to decrease the activity of sortase A by more than 50% at the concentration of 200  μM. The most promising compound was 2-(2-amino-3-chloro-benzoylamino)-benzoic acid which was able to inhibit S. aureus sortase A at the IC₅₀ value of 59.7  μM. This compound was selective toward sortase A compared to other four cysteine proteases - cathepsine L, cathepsine B, rhodesain, and SARS-CoV2 main protease. Microscale thermophoresis experiments confirmed that this compound bound sortase A with K_D value of 189 μM. Antibacterial and antibiofilm assays also confirmed high specificity of the hit compound against two standard and three wild-type, S. aureus hospital infection isolates. The effect of the compound on biofilms produced by two S. aureus ATCC strains was also observed suggesting that the compound reduced biofilm formation by changing the biofilm structure and thickness.       

• Identification of novel small-molecular inhibitors of Staphylococcus aureus sortase A using hybrid virtual screening. Volynets GP, Barthels F, Hammerschmidt SJ, Moshynets OV, Lukashov SS, Starosyla SA, Vyshniakova HV, Iungin OS, Bdzhola VG, Prykhod'ko AO, Syniugin AR, Sapelkin VM, Yarmoluk SM, Schirmeister T. The Journal of Antibiotics. 2022,  75: 321-332.