Identification of novel small-molecular inhibitors of Staphylococcus aureus sortase A using hybrid virtual screening

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 IC 50 value of 59.7 µM. This compound was selective toward sortase A compared to other four cysteine proteases – cathepsin L, cathepsin B, rhodesain, and the 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.

Screening and Identification of Natural Product‐Like Compounds as Potential Antibacterial Agents Targeting FemC of Staphylococcus aureus: An in‐Silico Approach

“…[12] Pharmacophore modeling and molecular docking followed by experimental study showed that 2-(2-amino-3-chlorobenzoylamino)benzoic acid exhibited IC 50 value of 59.7 μM for sortase A of S. aureus. [13] Rahman et al reported Lumacaftor, Dihydroergocornine, and Olaparib as potent molecules for S. aureus FemX. [15] Figure 8.…”

“…reported the molecules: PC‐124127620, PC‐124127795 and PC‐124127805) as potent candidate for dihydrofolate reductase of S. aureus [12] . Pharmacophore modeling and molecular docking followed by experimental study showed that 2‐(2‐amino‐3‐chlorobenzoylamino)‐benzoic acid exhibited IC 50 value of 59.7 μM for sortase A of S. aureus [13] . Rahman et al.…”

“…The integration of quantitative structure‐activity relationship (QSAR), molecular docking, dynamics, and free energy calculations yield the molecules (PC‐124127620, PC‐124127795, and PC‐124127805) for dihydrofolate reductase of S. aureus [12] . Hybrid virtual screening and experimental work revealed that 2‐(2‐amino‐3‐chlorobenzoylamino)‐benzoic acid has potency to inhibit sortase A of S. aureus [13] . Azole derivatives with naphthalene were reported as a promising candidate to develop antibacterial against S. aureus [14] .…”

“…[12] Hybrid virtual screening and experimental work revealed that 2-(2-amino-3-chlorobenzoylamino)-benzoic acid has potency to inhibit sortase A of S. aureus. [13] Azole derivatives with naphthalene were reported as a promising candidate to develop antibacterial against S. aureus. [14] Structure-based virtual screening, MD simulation, MM/GBSA, and quantum mechanics/molecular mechanics (QM/MM) study revealed that Lumacaftor, Dihydroergocornine, and Olaparib are the potent molecules against FemX of S. aureus.…”

An idea to explore: Engaging high school students in structure‐function studies of bacterial sortase enzymes and inhibitors ‐ A comprehensive computational experimental pipeline

“…There is a clear and pressing need to develop new antimicrobial agents to fight these pathogens. A potential candidate for therapeutic development in Gram‐positive bacteria are inhibitors of sortase enzymes 7–12 …”