β-Keto and β-hydroxyphosphonate analogs of biotin-5′-AMP are inhibitors of holocarboxylase synthetase

Sittiwong, Wantanee; Cordonier, Elizabeth L.; Zempleni, Janos; Dussault, Patrick H.

doi:10.1016/j.bmcl.2014.11.010

Cited by 13 publications

(12 citation statements)

References 31 publications

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“…However, progressing biotinol-5′-AMP 14 as drug candidate is limited by its activity against Hs BPL with K i = 0.42 μM and also difficulty of synthesis. Two other phosphonate-based isosteres, as in 15 and 16, respectively, were initially developed by Sittiwong et al for investigation of Hs BPL [ 39 ]. However, the β-ketophosphonate 15 and β-hydroxyphosphonate 16 analogues both showed reduced activity ( IC 50 of 39.7 μM and 203.7 μM, respectively) against Hs BPL compared to biotinol-5′-AMP 14 ( IC 50 = 7 μM against human BPL) [ 39 ].…”

Section: Bpl Inhibitors As New Antibacterialsmentioning

confidence: 99%

Biotin Protein Ligase Is a Target for New Antibacterials

et al. 2016

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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.

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Section: Bpl Inhibitors As New Antibacterialsmentioning

confidence: 99%

Biotin Protein Ligase Is a Target for New Antibacterials

et al. 2016

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“…12 Moreover, partial genetic inactivation of Mtb's ability to synthesize biotin was found to significantly enhance clearance of Mtb from lungs and spleen by rifampicin serving to validate MtBPL as a vulnerable target. 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).…”

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confidence: 99%

“…Bisubstrate inhibitors have been described for the structurally related BPL from Staphylococcus aureus including alkylphosphates, β-ketophosphonates, and triazole nucleosides, , as well as analogues wherein the adenosine nucleobase was replaced with benzoxazoline , and aryl moieties . We have reported 5′-[ N -( d -biotinoyl)sulfamoyl]amino-5′-deoxyadenosine (Bio-AMS, 1 , Figure A) is a potent subnanomolar bisubstrate inhibitor of the mycobacterial biotin protein ligase ( Mt BPL) .…”

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

et al. 2018

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5'-[ N-(d-biotinoyl)sulfamoyl]amino-5'-deoxyadenosine (Bio-AMS, 1) possesses selective activity against Mycobacterium tuberculosis ( Mtb) and arrests fatty acid and lipid biosynthesis through inhibition of the Mycobacterium tuberculosis biotin protein ligase ( MtBPL). Mtb develops spontaneous resistance to 1 with a frequency of at least 1 × 10 by overexpression of Rv3406, a type II sulfatase that enzymatically inactivates 1. In an effort to circumvent this resistance mechanism, we describe herein strategic modification of the nucleoside at the 5'-position to prevent enzymatic inactivation. The new analogues retained subnanomolar potency to MtBPL ( K = 0.66-0.97 nM), and 5' R- C-methyl derivative 6 exhibited identical antimycobacterial activity toward: Mtb H37Rv, MtBPL overexpression, and an isogenic Rv3406 overexpression strain (minimum inhibitory concentration, MIC = 1.56 μM). Moreover, 6 was not metabolized by recombinant Rv3406 and resistant mutants to 6 could not be isolated (frequency of resistance <1.4 × 10) demonstrating it successfully overcame Rv3406-mediated resistance.

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“… − A number of analogues of biotinyl-5′-AMP have recently been reported as inhibitors of BPL as shown in Figure . Some of these compounds have potential as antibacterial agents by inhibiting BPL from clinically important pathogens such as Staphylococcus aureus , Escherichia coli , , and Mycobacterium tuberculosis . , A range of bioisosteres have been investigated as replacements for the labile phosphoanhydride of biotinyl-5′-AMP 3 , including phosphodiester 4 , , hydroxyphosphonate 5 , ketophosphonate 6 , acylsulfamate 7 , and sulphonmyl amide 8 (Figure ). 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. ,, …”

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

Feng

Paparella²,

Tieu

et al. 2016

ACS Med. Chem. Lett.

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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

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β-Keto and β-hydroxyphosphonate analogs of biotin-5′-AMP are inhibitors of holocarboxylase synthetase

Cited by 13 publications

References 31 publications

Biotin Protein Ligase Is a Target for New Antibacterials

Biotin Protein Ligase Is a Target for New Antibacterials

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

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

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