1,737 research outputs found
Mechanisms governing precise protein biotinylation
No full textAbstract not availableLouise M. Sternicki, Kate L. Wegener, John B. Bruning, Grant W. Booker and Steven W. Polya
A hypoxia-activated antibacterial prodrug
No full textA prodrug based on a known antibacterial compound is reported to target Staphylococcus aureus and Escherichia coli under reductive conditions. The prodrug was prepared by masking the N-terminus and side chain amines of a component lysine residue as 4-nitrobenzyl carbamates. Activation to liberate the antibacterial was demonstrated on treatment with a model reductant, tin(II) chloride. The bioactivity of 1 was confirmed in antibacterial susceptibility assays whereas prodrug 2 was inactive.Yuan Qi Yeoh, John R. Horsley, Steven W. Polyak, Andrew D. Abel
Biotin protein ligase is a target for new antibacterials
No full textThere 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.Jiage Feng, Ashleigh S. Paparella, Grant W. Booker, Steven W. Polyak, and Andrew D. Abel
The role of biotin in bacterial physiology and virulence: A novel antibiotic target for Mycobacterium tuberculosis
No full textTuberculosis (TB) is a global pandemic that ranks alongside HIV-AIDS and malaria as the leading cause of death by infectious disease, with the highest incidence rates observed in Southeast Asian, African, and Western Pacific countries ( 1 ). In 1993 the WHO declared TB to be a global health emergency and set the Millennium Development Goal of reducing the prevalence and mortality rates to 50% of those observed in 1990 by the 2015 deadline ( 2 ). Although the rates of new TB cases and mortality have declined over the past decade and are within reach of the 2015 target, the number of TB patients and the prevalence of drug-resistant strains are rising ( 3 ). Multidrug-resistant TB (MDR-TB) must be addressed now as a public health crisis to achieve the ambitious Millennium Development Goal target of complete elimination of TB as a public health concern by 2050 ( 4 ).Wanisa Salaemae, Grant W. Booker, and Steven W. Polya
Synergistic effect of 14-alpha-lipoyl andrographolide and various antibiotics on the formation of biofilms and production of exopolysaccharide and pyocyanin by Pseudomonas aeruginosa
No full textPseudomonas aeruginosa produces a biofilm that provides the bacteria with an effective barrier against antibiotics. Here, we investigated the synergy of various antibiotics with 14-alpha-lipoyl andrographolide (AL-1), focusing upon synthesis of the biofilm. AL-1 also inhibited the production of the exopolysaccharide and pyocyanin components. We propose that AL-1 may potentially serve as a cotherapy to combat P. aeruginosa.Xiangping Zeng, Xiangyang Liu, Jiang Bian, Gang Pei, Huanqin Dai, Steven W. Polyak, Fuhang Song, Li Ma, Yuqiang Wang, and Lixin Zhan
5-Benzylidenerhodanine and 5-benzylidene-2-4-thiazolidinedione based antibacterials
No full textHerein we outline the antibacterial activity of amino acid containing thiazolidinediones and rhodanines against Gram-positive bacteria Staphylococcus aureus ATCC 31890, Staphylococcus epidermidis and Bacillus subtilis ATCC 6633. The rhodanine derivatives were generally more active than the analogous thiazolidinediones. Compounds of series 5 showed some selectivity for Bacillus subtilis ATCC 6633, the extent of which is enhanced by the inclusion of a non-polar amino acid at the 5-position of the core thiazolidinediones and rhodanines scaffolds. SAR data of series 8 demonstrated improved activity against the clinically more significant Staphylococci with selectivity over Bacillus subtilis ATCC 6633 induced by introduction of a bulky aryl substituent at the 5-position of the core scaffolds. © 2012 Elsevier Ltd. All rights reserved.Ondrej Zvarec, Steven W. Polyak, William Tieu, Kevin Kuan, Huanqin Dai, Daniel Sejer Pedersen, Renato Morona, Lixin Zhang, Grant W. Booker, Andrew D. Abel
Optimising in situ click chemistry: the screening and identification of biotin protein ligase inhibitors
No full textData source: Supplementary information, https://doi.org/10.1039/c3sc51127hA 'leaky mutant' (SaBPL-R122G) of Staphylococcus aureus biotin protein ligase (SaBPL) is used to enhance the turnover rate for the reaction of biotin alkyne with an azide to give a triazole. This allows the enzyme to select the optimum triazole-based inhibitor using a library of such azides in a single experiment with greatly improved efficiency and sensitivity of detection, difficulties that can restrict the general utility of a multi-component in situ click approach to ligand optimisation.William Tieu, Tatiana P. Soares da Costa, Min Y. Yap, Kelly L. Keeling, Matthew C. J. Wilce, John C. Wallace, Grant W. Booker, Steven W. Polyak and Andrew D. Abel
New series of BPL inhibitors to probe the ribose-binding pocket of Staphylococcus aureus biotin protein ligase
No full textLink to a related website: http://europepmc.org/articles/pmc5150696?pdf=render, Open Access via UnpaywallReplacing 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.Jiage Feng, Ashleigh S. Paparella, William Tieu, David Heim, Sarah Clark, Andrew Hayes, Grant W. Booker Steven W. Polyak and Andrew D. Abel
Biotin biosynthesis in Mycobacterium tuberculosis: Physiology, biochemistry and molecular intervention
No full textBiotin is an important micronutrient that serves as an essential enzyme cofactor. Bacteria obtain biotin either through de novo synthesis or by active uptake from exogenous sources. Mycobacteria are unusual amongst bacteria in that their primary source of biotin is through de novo synthesis. Here we review the importance of biotin biosynthesis in the lifecycle of Mycobacteria. Genetic screens designed to identify key metabolic processes have highlighted a role for the biotin biosynthesis in bacilli growth, infection and survival during the latency phase. These studies help to establish the biotin biosynthetic pathway as a potential drug target for new anti-tuberculosis agents.Wanisa Salaemae, Al Azhar, Grant W. Booker, Steven W. Polya
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