Inhibition of Dethiobiotin Synthase (DTBS): Toward Next-Generation Antituberculosis Agents.

dethiobiotin synthase (DTBS) is a crucial enzyme involved in the biosynthesis of biotin in the causative agent of tuberculosis, . Here, we report a binder of DTBS, cyclopentylacetic acid ( = 3.4 ± 0.

Biochemical characterisation of class III biotin protein ligases from Botrytis cinerea and Zymoseptoria tritici.

Biotin protein ligase (BPL) is an essential enzyme in all kingdoms of life, making it a potential target for novel anti-infective agents. Whilst bacteria and archaea have simple BPL structures (class I and II), the homologues from certain eukaryotes such as mammals, insects and yeast (class III) have evolved a more complex structure with a large extension on the N-terminus of the protein in addition to the conserved catalytic domain. The absence of atomic resolution structures of any class III BPL hinders structural and functional analysis of these enzymes.

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

Biotin protein ligase (BPL) inhibitors are a novel class of antibacterial that target clinically important methicillin-resistant () In BPL is a bifunctional protein responsible for enzymatic biotinylation of two biotin-dependent enzymes, as well as serving as a transcriptional repressor that controls biotin synthesis and import. In this report, we investigate the mechanisms of action and resistance for a potent anti-BPL, an antibacterial compound, biotinyl-acylsulfamide adenosine (BASA). We show that BASA acts by both inhibiting the enzymatic activity of BPL in vitro as well as functioning as a transcription co-repressor.

Identification and targeted management of a neurodegenerative disorder caused by biallelic mutations in SLC5A6.

We describe a sibling pair displaying an early infantile-onset, progressive neurodegenerative phenotype, with symptoms of developmental delay and epileptic encephalopathy developing from 12 to 14 months of age. Using whole exome sequencing, compound heterozygous variants were identified in , which encodes the sodium-dependent multivitamin transporter (SMVT) protein. SMVT is an important transporter of the B-group vitamins biotin, pantothenate, and lipoate.

Sulfonamide-Based Inhibitors of Biotin Protein Ligase as New Antibiotic Leads.

Here, we report the design, synthesis, and evaluation of a series of inhibitors of BPL (BPL), where the central acyl phosphate of the natural intermediate biotinyl-5'-AMP () is replaced by a sulfonamide isostere. Acylsulfamide () and amino sulfonylurea () showed potent inhibitory activity ( = 0.007 ± 0.