We report the synthesis and evaluation of 5-halogenated-1,2,3-triazoles as inhibitors of biotin protein ligase from Staphylococcus aureus. The halogenated compounds exhibit significantly improved antibacterial activity over their nonhalogenated counterparts. Importantly, the 5-fluoro-1,2,3-triazole compound 4c displays antibacterial activity against S. aureus ATCC49775 with a minimum inhibitory concentration (MIC) of 8 μg/mL.
Replacing the labile adenosinyl-substituted phosphoanhydride of biotinyl-5′-AMP with a N1-benzyl substituted 1,2,3-triazole gave a new truncated series of inhibitors of Staphylococcus aureus biotin protein ligase (SaBPL). The benzyl group presents to the ribose-binding pocket of SaBPL based on in silico docking. Halogenated benzyl derivatives (12t, 12u, 12w, and 12x) proved to be the most potent inhibitors of SaBPL. These derivatives inhibited the growth of S. aureus ATCC49775 and displayed low cytotoxicity against HepG2 cells. A number of analogues of biotinyl-5′-AMP have recently been reported as inhibitors of BPL as shown in Figure 2. Some of these compounds have potential as antibacterial agents by inhibiting BPL from clinically important pathogens such as Staphylococcus aureus, 6 Escherichia coli, 7,8 and Mycobacterium tuberculosis. 9,10 A range of bioisosteres have been investigated as replacements for the labile phosphoanhydride of biotinyl-5′-AMP 3, including phosphodiester 4, 11,12 hydroxyphosphonate 5, 13 ketophosphonate 6, 13 acylsulfamate 7, 11 and sulphonmyl amide 8 10 (Figure 2). We have also reported biotin triazoles (e.g., 9−11) as a novel class of BPL inhibitor that selectively targets BPL from the clinically important bacterial pathogen Staphylococcus aureus over the human homologue. 3,14,15 Without exception, all isostere-based BPL inhibitors reported to date contain a biotin and an adenine group, or analogue thereof, as discussed above and as shown in Figure 2. These two groups occupy well-defined binding pockets in the enzyme as per biotinyl-5′-AMP 3, as supported by X-ray crystallographic and mutagenesis studies. 3,16 The ribose group of the triazole series can be removed as in 10, and the adenine can be modified as in 11, which has improved stability and >1000-fold specificity for the BPL from S. aureus over the human homologue. 3 We now report the first examples of truncated 1,2,3-triazole-based BPL inhibitors with a 1-benzyl substituent
There is a desperate need for novel antibiotic classes to combat the rise of drug resistant pathogenic bacteria, such as Staphylococcus aureus. Inhibitors of the essential metabolic enzyme biotin protein ligase (BPL) represent a promising drug target for new antibacterials. Structural and biochemical studies on the BPL from S. aureus have paved the way for the design and development of new antibacterial chemotherapeutics. BPL employs an ordered ligand binding mechanism for the synthesis of the reaction intermediate biotinyl-5′-AMP from substrates biotin and ATP. Here we review the structure and catalytic mechanism of the target enzyme, along with an overview of chemical analogues of biotin and biotinyl-5′-AMP as BPL inhibitors reported to date. Of particular promise are studies to replace the labile phosphoroanhydride linker present in biotinyl-5′-AMP with alternative bioisosteres. A novel in situ click approach using a mutant of S. aureus BPL as a template for the synthesis of triazole-based inhibitors is also presented. These approaches can be widely applied to BPLs from other bacteria, as well as other closely related metabolic enzymes and antibacterial drug targets.
Here, we report the design, synthesis, and evaluation of a series of inhibitors of Staphylococcus aureus BPL (SaBPL), where the central acyl phosphate of the natural intermediate biotinyl-5′-AMP ( 1) is replaced by a sulfonamide isostere. Acylsulfamide (6) and amino sulfonylurea (7) showed potent in vitro inhibitory activity (K i = 0.007 ± 0.003 and 0.065 ± 0.03 μM, respectively) and antibacterial activity against S. aureus ATCC49775 with minimum inhibitory concentrations of 0.25 and 4 μg/mL, respectively. Additionally, the bimolecular interactions between the BPL and inhibitors 6 and 7 were defined by X-ray crystallography and molecular dynamics simulations. The high acidity of the sulfonamide linkers of 6 and 7 likely contributes to the enhanced in vitro inhibitory activities by promoting interaction with SaBPL Lys187. Analogues with alkylsulfamide (8), β-ketosulfonamide (9), and β-hydroxysulfonamide (10) isosteres were devoid of significant activity. Binding free energy estimation using computational methods suggests deprotonated 6 and 7 to be the best binders, which is consistent with enzyme assay results. Compound 6 was unstable in whole blood, leading to poor pharmacokinetics. Importantly, 7 has a vastly improved pharmacokinetic profile compared to that of 6 presumably due to the enhanced metabolic stability of the sulfonamide linker moiety.
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