Abstract
Fluoroquinolones are very important drugs in the clinical antibacterial arsenal; their success is principally due to their mode of action: the stabilisation of a gyrase-DNA intermediate (the cleavage complex), which triggers a chain of events leading to cell death. Microcin B17 (MccB17) is a modified peptide bacterial toxin that acts by a similar mode of action, but is unfortunately unsuitable as a therapeutic drug. However, its structure and mechanism could inspire the design of new antibacterial compounds that are needed to circumvent the rise in bacterial resistance to current antibiotics. Here we describe the investigation of the structural features responsible for MccB17 activity and the identification of fragments of the toxin that retain the ability to stabilise the cleavage complex.
Highlights
DNA gyrase and DNA topoisomerase IV are enzymes belonging to the DNA topoisomerase family, responsible for the regulation of DNA topology in all cells [1,2]
There are a limited number of bacterial toxins that are known to stabilise the gyrase-DNA cleavage complex: among them are the protein CcdB [9,10] and the peptide toxin microcin B17 [11]
Microcin B17 (MccB17), recombinantly produced MccB17 was hydrolysed with aqueous sodium hydroxide solution; the mixture obtained after neutralization and lyophilisation was tested for inhibitory activity on DNA gyrase
Summary
DNA gyrase and DNA topoisomerase (topo) IV are enzymes belonging to the DNA topoisomerase family, responsible for the regulation of DNA topology in all cells [1,2]. The success of the fluoroquinolones is due to the fact that they stabilise a transient topoisomerase-DNA covalent complex that can lead to the lethal release of broken DNA [6] This intermediate is referred to as the cleavage complex: a covalent adduct where both strands of the DNA have been cut and linked to the enzyme, forming a gate through which another segment of DNA can be passed (the strand-passage event) to alter DNA topology. Other antibacterials that inhibit gyrase by different mechanisms are referred to as catalytic inhibitors These include the aminocoumarins, such as novobiocin, that compete with ATP binding [7] and simocyclinone D8, a related antibiotic that prevents DNA from binding to the enzyme [8]. There are a limited number of bacterial toxins that are known to stabilise the gyrase-DNA cleavage complex: among them are the protein CcdB [9,10] and the peptide toxin microcin B17 [11]
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