A New 1,2,3-Triazole Scaffold with Improved Potency against Staphylococcus aureus Biotin Protein Ligase

Abstract

Staphylococcus aureus, a key ESKAPE bacteria, is responsible for most blood-based infections and, as a result, is a major economic healthcare burden requiring urgent attention. Here, we report in silico docking, synthesis, and assay of N1-diphenylmethyl triazole-based analogues (7–13) designed to interact with the entire binding site of S. aureus biotin protein ligase (SaBPL), an enzyme critical for the regulation of gluconeogenesis and fatty acid biosynthesis. The second aryl ring of these compounds enhances both SaBPL potency and whole cell activity against S. aureus relative to previously reported mono-benzyl triazoles. Analogues 12 and 13, with added substituents to better interact with the adenine binding site, are particularly potent, with K i values of 6.01 ± 1.01 and 8.43 ± 0.73 nM, respectively. These analogues are the most active triazole-based inhibitors reported to date and, importantly, inhibit the growth of a clinical isolate strain of S. aureus ATCC 49775, with minimum inhibitory concentrations of 1 and 8 μg/mL, respectively.

Structural Study of Potent Triazole-Based Inhibitors of Staphylococcus aureus Biotin Protein Ligase

“…Notably, substituting the p-carboxy acid of the aryl group of an N1-diphenylmethyl-1,2,3-triazole with an imidazole or aminopyridine group, as in 6 and 7, resulted in the most potent triazole-based SaBPL inhibitors reported to date (K i = 6.01 ± 1.01 and 8.43 ± 0.73 nM, respectively). 22 Furthermore, triazoles 6 and 7 exhibited excellent whole-cell activity against a clinical isolate strain of S. aureus, ATCC 49775 (MIC = 1 and 8 μg/mL, 22 respectively), superior to those of previously reported triazole-based inhibitors. 20 The nanomolar potency exhibited by triazoles 6 and 7 is likely associated with hydrogen-bonding interactions between the respective imidazole/aminopyridine groups and N212/S128 in the adenine binding site of SaBPL.…”

“…Crucially, triazoles 6 and 7 are also reported to potentially hydrogen-bond both N212 and S128. 22 An approximate 25fold loss in activity was apparent for pentanamide 15 compared to the butanamide substituent of 14 (K i = 246 ± 22 vs 10 ± 2 nM, respectively). This drop in potency is consistent with docking, where the pentanamide was predicted to interact only with S128.…”

“…In silico docking indicates that the imidazole and aminopyridine groups of highly potent N1-diphenylmethyl-triazoles 6 and 7 hydrogen-bond with N212 and S128 in the adenine pocket of SaBPL. 22 This suggests that replacing these groups with a range of other hydrogen-bond donor (HBD) and acceptor (HBA) substituents (see 9−19 in Figure 2) warrants further investigation. Triazoles 8−19 were docked in silico into the SaBPL active site (PDB entry 6APW 20 ) using ICM-Pro in order to identify hydrogen bonding within the adenine binding site, and the results are discussed below (see the Supporting Information for the docking protocol).…”

“…The nanomolar potency exhibited by triazoles 6 and 7 is likely associated with hydrogen-bonding interactions between the respective imidazole/aminopyridine groups and N212/S128 in the adenine binding site of Sa BPL. Analogous interactions between N212/S128 and the adenine of the natural intermediate 1 are also apparent. , However, further work is required to investigate whether establishing interactions with N212 and S128 manifests in potent N1 -diphenylmethyl-1,2,3-triazole Sa BPL inhibitors.…”

“…20 Our recently reported N1-diphenylmethyl-1,2,3-triazole series addressed this finding by combining the aryl ring functionalities of both benzyl triazoles 4 and 5 into one structure. 22 The two aryl groups then occupy both the adenosine binding pocket and the adjacent binding site. Notably, substituting the p-carboxy acid of the aryl group of an N1-diphenylmethyl-1,2,3-triazole with an imidazole or aminopyridine group, as in 6 and 7, resulted in the most potent triazole-based SaBPL inhibitors reported to date (K i = 6.01 ± 1.01 and 8.43 ± 0.73 nM, respectively).…”