Polymyxin B lethality requires energy-dependent outer membrane disruption
Borrelli, C.; Douglas, E. J. A.; Riley, S. M. A.; Lemonidi, A. E.; Larrouy-Maumus, G. B.; Lu, W.-J.; Bonev, B. B.; Edwards, A. M.; Hoogenboom, B. W.
Show abstract
Polymyxin antibiotics target lipopolysaccharide (LPS) in both membranes of the bacterial cell envelope, leading to bacterial killing through a mechanism that remains poorly understood. Here, we demonstrate that metabolic activity is essential for polymyxin lethality and leverage this insight to determine its mode of action. Polymyxin B (PmB) efficiently killed exponential phase E. coli but was unable to eliminate stationary phase cells unless a carbon source was available. Antibiotic lethality correlated with surface protrusions, LPS loss, and a significant reduction in outer membrane (OM) barrier function, processes that required LPS synthesis and transport. While the energy-dependent OM disruption was not directly lethal, it facilitated PmB access to the inner membrane (IM), which the antibiotic permeabilised in an energy-independent manner, leading to cell death. Finally, we show that the polymyxin resistance determinant MCR-1 prevents PmB-mediated LPS loss and OM protrusions and thereby renders the antibiotic ineffective.
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