Optimisation of a Novel Class of DNA Gyrase Inhibitors to Improve Antibacterial Activity

As antibiotic resistance continues to rise, the need for new antibacterials is clear. In this context, Gram-negative bacteria pose a specific challenge due to their multiple possible resistance mechanisms and unique outer membrane. Poor outer membrane permeability limits the activity of many antibiotics. This has led to a growing interest in identifying structural features capable of enhancing small molecule antibiotics' ability to cross the Gram-negative outer membrane. Examples of such approaches include the incorporation of ionisable amines to promote uptake and the attachment of siderophore moieties to exploit bacterial iron-transport systems. Here, we apply these strategies to a newly discovered class of potent DNA gyrase inhibitors known as the isoquinoline sulphonamides, typified by the compound LEI-800, with the aim of enhancing its Gram-negative activity. In doing so, the distal aromatic ring of the LEI-800 scaffold was functionalised with primary amine, guanidine and siderophore moieties. These studies reveal that the introduction of an ionisable amine group is tolerated at selected positions of the LEI-800 scaffold, resulting in an increased antibacterial activity and mitigating membrane permeability barriers.