New Series of BPL Inhibitors To Probe the Ribose-Binding Pocket of Staphylococcus aureus Biotin Protein Ligase

Abstract

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

Avoiding Antibiotic Inactivation in Mycobacterium tuberculosis by Rv3406 through Strategic Nucleoside Modification

“…12 Bisubstrate inhibitors have been described for the structurally related BPL from Staphylococcus aureus including alkylphosphates, 13 β-ketophosphonates, 14 and triazole nucleosides, 15,16 as well as analogues wherein the adenosine nucleobase was replaced with benzoxazoline 17,18 and aryl moieties. 19 We have reported 5′-[N-(D-biotinoyl)sulfamoyl]amino-5′-deoxyadenosine (Bio-AMS, 1, Figure 1A) is a potent subnanomolar bisubstrate inhibitor of the mycobacterial biotin protein ligase (MtBPL). 20 Bio-AMS possesses excellent antitubercular activity against Mtb H37Rv and MDR/XDR-TB strains with minimum inhibitory concentrations (MICs) ranging from 0.16 to 0.625 μM and is not affected by changes to the primary carbon source.…”

A Novel Lipoate-Protein Ligase, Mhp-LplJ, Is Required for Lipoic Acid Metabolism in Mycoplasma hyopneumoniae

“…Previous reports indicated that suppressors of essential metabolic enzymes could be developed as new classes of antibiotics. For example, BPLs have been studied for a few years as drug targets for new antibiotics ( Costa et al, 2012 ; Feng et al, 2016a , b ). Studies have shown that biotin analogs, as inhibitors of BPL, have significant antibacterial activity against M. tuberculosis ( Duckworth et al, 2011 ; Bockman et al, 2015 ), E. coli ( Xu and Beckett, 1994 ; Brown and Beckett, 2005 ), S. aureus ( Costa et al, 2012 ; Pendini et al, 2013 ; Paparella et al, 2014 ), and so on.…”

Advanced Resistance Studies Identify Two Discrete Mechanisms in Staphylococcus aureus to Overcome Antibacterial Compounds that Target Biotin Protein Ligase

“…Three lines of evidence were consistent with BASA acting through direct binding to the BPL target. Firstly, the compound showed reduced antibacterial activity against a strain of S. aureus engineered to overexpress SaBPL [19]. The increased concentration of recombinant BPL in the bacteria elevated the MIC by eight-fold over an isotypic control strain ( Figure S5A).…”

“…ACC and BPL have been identified as essential gene products for growth in genetic knockout studies performed on S. aureus [9][10][11][12] and, consequently, have been the targets of drug discovery programs. The antibacterial efficacy of ACC inhibitors has been demonstrated in vivo (reviewed in [13,14]) and BPL inhibitors have shown efficacy in vitro against S. aureus and M. tuberculosis [15][16][17][18][19]. Whilst dispensable for growth in culture, PC has been shown to be an important virulence factor in bacteremia models in mice and nematodes [20,21].…”

“…Several groups have reported on the development of anti-BPL compounds with antibacterial activity [15][16][17][18][19][30][31][32][33][34]. Bisubstrate analogs that occupy both the biotin and ATP-binding pockets and mimic the mode of binding adopted by biotinyl-5 -AMP have been particularly promising.…”