The Optimisation and Derivative Design of Lead Compounds to Inhibit Staphylococcus aureus Surface Proteins Using Computational Tools

Atopic dermatitis (AD), also known as eczema, is a genetically transmitted chronic skin disorder that is associated with other conditions such as asthma and allergic rhinitis. It affects people at all stages of life and can seriously impair quality of life due to repeated itching and scratching resulting in crusted lesions and sleep loss. Staphylococcus aureus colonisation on the skin of patients with AD exacerbates the symptoms. Current treatments for S. aureus colonised AD skin are antibiotics, however resistance in S. aureus has been reported. Clumping factor B (ClfB), a S. aureus surface protein, is an important virulence factor for AD skin colonisation and ligands for ClfB are exposed on AD skin. Allantodapsone is a lead compound that inhibits ClfB and clumping factor A (ClfA), however, there are toxicity concerns regarding the compounds structure. Therefore, derivatives of allantodapsone and other derivatives were investigated in silico and in vitro.

Analysis of all of the ClfB and ClfA crystal structures was carried out and docking studies performed for the previously identified compounds allantodapsone, MB03, MMV006962 and MMV019241. Furthermore, docking of proposed allantodapsone and MB03 derivatives was also performed. A fragment based approach to MB03 derivative design was also used. Synthesised allantodapsone derivatives were tested in vitro for their inhibitory activity on ClfB mediated S. aureus adhesion to the loricrin loop region L2V. Three allantodapsone-ClfB binding modes were identified, as well as binding modes for ClfA. Binding modes for MB03, MMV006962 and MMV019241 with ClfB and ClfA were also identified. Based on molecular docking analysis and fragment based design, two derivatives of allantodapsone (thioether and ether) and five derivatives of MB03 were proposed as likely to improve binding. A range of similar compounds to allantodapsone were tested. One of the eleven synthesised compounds (FBCI) displayed ClfB inhibition in vitro. Models of Fibronectin Binding Protein B (FnBPB) in apo and bound forms were generated and validated. Subsequent molecular docking predicted inhibitors of ClfA and ClfB to also bind FnBPA and FnBPB. This suggests that these compounds may act as pan-inhibitors similar to some of the peptide ligands that bind to the receptors.