Biotin Analogues with Antibacterial Activity Are Potent Inhibitors of Biotin Protein Ligase

Costa, Tatiana P. Soares da; Tieu, William; Yap, Min; Zvarec, Ondrej; Bell, Jan M.; Turnidge, John; Wallace, John C.; Booker, Grant W.; Wilce, Matthew C. J.; Abell, Andrew D.; Polyak, Steven W.

doi:10.1021/ml300106p

Cited by 41 publications

(65 citation statements)

References 24 publications

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“…Further, the mainchain of the ABL loop is in the same position even in the absence of the adenosyl moiety (the sidechains of this loop were not defined in the electron density). These structures, together with a recently reported structure of Sa BPL with biotin‐based ligands bound in the active site, show that any biotin ligand is sufficient to stabilize the BBL and to result in the formation of an Sa BPL dimer.…”

Section: Resultssupporting

confidence: 57%

Structural characterization of Staphylococcus aureus biotin protein ligase and interaction partners: An antibiotic target

et al. 2013

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The essential metabolic enzyme biotin protein ligase (BPL) is a potential target for the development of new antibiotics required to combat drug-resistant pathogens. Staphylococcus aureus BPL (SaBPL) is a bifunctional protein, possessing both biotin ligase and transcription repressor activities. This positions BPL as a key regulator of several important metabolic pathways. Here, we report the structural analysis of both holo- and apo-forms of SaBPL using X-ray crystallography. We also present small-angle X-ray scattering data of SaBPL in complex with its biotin-carboxyl carrier protein substrate as well as the SaBPL:DNA complex that underlies repression. This has revealed the molecular basis of ligand (biotinyl-5'-AMP) binding and conformational changes associated with catalysis and repressor function. These data provide new information to better understand the bifunctional activities of SaBPL and to inform future strategies for antibiotic discovery.

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Section: Resultssupporting

confidence: 57%

Structural characterization of Staphylococcus aureus biotin protein ligase and interaction partners: An antibiotic target

et al. 2013

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“…In a study seeking to validate biotin biosynthesis as a potential target for the development of new antibiotics, the authors have demonstrated that de novo biotin synthesis is essential for M. tuberculosis to establish and maintain a chronic infection [144]. In another study, analogs of biotin have been synthesized and have demonstrated antimicrobial activity through the inhibition of biotin protein ligase (BPL) [145]. Taken together, there appears to be a great potential for targeting biotin biosynthesis, not only in antibacterial drug development but perhaps fungal BPL could serve as a potential drug development target for new antifungal agents.…”

Section: Miscellaneous Antifungal Agentsmentioning

confidence: 99%

The Mechanistic Targets of Antifungal Agents: An Overview

Mazu¹,

Bricker²,

Flores‐Rozas³

et al. 2016

MRMC

162

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Pathogenic fungi are a major causative group for opportunistic infections (OIs). AIDS patients and other immunocompromised individuals are at risk for OIs, which if not treated appropriately, contribute to the mortality associated with their conditions. Several studies have indicated that the majority of HIV-positive patients contract fungal infections throughout the course of their disease. Similar observations have been made regarding the increased frequency of bone marrow and organ transplants, the use of antineoplastic agents, the excessive use of antibiotics, and the prolonged use of corticosteroids among others. In addition, several pathogenic fungi have developed resistance to current drugs. Together these have conspired to spur a need for developing new treatment options for OIs. To aid this effort, this article reviews the biological targets of current and emerging drugs and agents that act through these targets for the treatment of opportunistic fungal infections.

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“…20 The antibacterial activity of the compounds was also determined using S. aureus strain ATCC 49775. 18 Growth of the bacteria 20 h post-treatment was measured spectrophotometrically at 600 …”

Section: B Iotin Protein Ligase (Bpl) Catalyzes the Reaction Of Biotinmentioning

confidence: 99%

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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Biotin Analogues with Antibacterial Activity Are Potent Inhibitors of Biotin Protein Ligase

Cited by 41 publications

References 24 publications

Structural characterization of Staphylococcus aureus biotin protein ligase and interaction partners: An antibiotic target

Structural characterization of Staphylococcus aureus biotin protein ligase and interaction partners: An antibiotic target

The Mechanistic Targets of Antifungal Agents: An Overview

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

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