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Therapeutics


Figure 1


Comparison of the cell walls of Gram-negative and Gram- positive bacteria. The relatively-impermeable cell wall of Gram-negative bacteria renders the organisms more resistant to antibiotics


in a Phase I clinical trial, sensitises Gram-negative bacteria to antibiotics normally excluded by the outer membrane. Prior to initiating our clinical trial, we used bac- terial cytological profiling (BCP), a microscopy- based technique that provides insight into the mechanism of action for antibacterial compounds, to define how SPR741 enhances sensitivity of Gram-negative bacteria to Gram-positive antibi- otics. In this study, we assessed SPR741 alone and in combination with fluorescently-labelled azithromycin (a macrolide) or Bocillin (a peni-


cillin), to observe uptake into Escherichia coli. Cytological profiling and cytometry results demon- strated that SPR741 permeabilises the outer mem- brane of Gram-negative bacteria, such as E.coli, allowing normally impenetrant antibacterials into the periplasm and cytoplasm (Figure 3). Preclinical studies show that by disrupting the outer membrane, SPR741 enables more than two- dozen classes of existing antibiotics normally only effective against Gram-positive bacteria to enter and destroy the now-relatively defenceless Gram- negative bacteria.


Figure 2 Potentiator molecules specifically interact with the outer membrane of Gram- negative bacteria to increase the membrane’s permeability, allowing Gram-positive antibiotics to enter and kill the cell


Drug Discovery World Summer 2017


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