Abstract
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.
Highlights
Infectious diseases caused by pathogenic bacteria, such as Staphylococcus aureus, are a major threat to human health
The spread of antibiotic resistant strains, such as methicillin resistant S. aureus (MRSA), is problematic with resistance having been developed to most penicillin-based antibiotics [1,2]
This review presents biotin protein ligase (BPL) as a novel drug target, and discusses the design of small molecule inhibitors for antibacterial discovery
Summary
Infectious diseases caused by pathogenic bacteria, such as Staphylococcus aureus, are a major threat to human health. Biotin-activated PC gluconeogenesis and amino acid biosynthesis [14] These metabolic pathways are essential for the is involved in the conversion of pyruvate to oxaloacetate required in the citric acid cycle that is central survival and virulence of S. aureus, and, as such, BPL presents as an attractive drug target for new to a number of key metabolic pathways, such as gluconeogenesis and amino acid biosynthesis [14]. In the absence of non-biotinylated biotin-dependent enzymes, S. aureus BPL (SaBPL) can that controls the uptake and biosynthesis of biotin by binding specific DNA sequences in the form a dimer that is responsive to DNA binding.
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