The top image depicts untreated E. coli; the bottom image shows the same bacterium after 90 minutes of exposure to the antibiotic polymyxin B.
Carolina Borrelli, Edward Douglas et al./Nature Microbiology
The mechanism by which polymyxins, a class of antibiotics, breach the defenses of bacteria has been revealed through high-resolution microscopy, offering new insights for developing treatments against drug-resistant infections.
Polymyxins are typically reserved as last-line treatments for certain gram-negative bacteria responsible for serious infections such as pneumonia, meningitis, and typhoid fever. As noted by Andrew Edwards from Imperial College London, âThe top three World Health Organization priority pathogens are all gram-negative bacteria, reflecting their complex cell envelope.â
These bacteria possess an outer membrane made of lipopolysaccharides, which functions as a barrier. While it’s known that polymyxins target this layer, the specific mechanisms by which they disrupt it and kill the bacteria were previously unclear. Additionally, it was uncertain why these drugs sometimes failed.
In research conducted by Edwards and his team, they employed biochemical assays and atomic force microscopy to discover that polymyxin B, one of the two polymyxins approved for clinical use, triggers the formation of bulges on the surface of gram-negative bacteria like E. coli.
Shortly after the appearance of these protrusions, the bacteria began shedding lipopolysaccharides, evident in the surrounding solution.
The team concluded that the presence of the antibiotic prompts the bacteria to accelerate the incorporation of lipopolysaccharide “bricks” into their protective exterior. However, this rapid construction coincides with the loss of some bricks, creating temporary vulnerabilities for the antibiotic to penetrate and kill the cells.
âThe antibiotics act like a crowbar that facilitates the removal of these bricks from the wall,â Edwards noted. “The outer membrane doesnât collapse entirely; it doesnât fall off. However, there are observable gaps that allow the antibiotic to access the inner membrane.”
The researchers also identified a critical reason for the antibioticâs variable efficacy: it predominantly affects bacteria that are actively growing. In contrast, when bacteria enter a dormant stateâoften as a survival tactic against environmental challenges like nutrient shortagesâpolymyxin B loses its effectiveness because the bacteria halt armour production.
Images showing the changes to the outer layer of E. coli exposed to polymyxin B over time, from untreated to 90 minutes post-exposure.
Carolina Borrelli, Edward Douglas et al. / Nature Microbiology
Interestingly, the researchers found that supplying sugars to dormant E. coli cells could spur them back into activity, resuming lipopolysaccharide construction, and leaving them vulnerable to polymyxin B within just 15 minutes. This phenomenon may also apply to polymyxin E, the other polymyxin in clinical use.
Edwards suggests that while targeting dormant bacteria with sugars to reawaken them could be a strategy, it comes with risks, as it may lead to rapid bacterial proliferation at infection sites. Instead, he proposes exploring combination therapies that could bypass the dormant state without triggering increased bacterial growth.
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