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
11
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72