The way antibiotics called polymyxins pierce the armour of bacteria has been revealed in stunning detail by high-resolution microscopy, which could help us develop new treatments for drug-resistant infections.
Polymyxins are commonly used as a last-resort treatment against some so-called gram-negative bacteria, which can cause infections such as pneumonia, meningitis and typhoid fever. 鈥淭he top three World 午夜福利1000集合 Organization priority pathogens are all gram-negative bacteria, and this is largely a reflection of their complex cell envelope,鈥� says at Imperial College London.
Around their inner cell, these bacteria have an outer surface layer containing molecules called lipopolysaccharides, which act like armour. We knew polymyxins target this outer layer, but how exactly they disrupt it and then kill bacteria wasn鈥檛 understood; neither was why the drugs don鈥檛 always work.
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Now, Edwards and his colleagues have used biochemical experiments and atomic force microscopy 鈥� in which a needle just a few nanometres wide creates an image of a cell by sensing its shape 鈥� to reveal that one of the two types of polymyxin used therapeutically, called polymyxin B, causes strange bulges to break out on the surface of the gram-negative bacterium E. coli.
Minutes after the protrusions appear, the bacterium begins to quickly shed its lipopolysaccharides, which the researchers detected in the solution it was in.
The researchers say the antibiotic鈥檚 presence triggers the bacterium to try to put more and more 鈥渂ricks鈥� of lipopolysaccharide in its defensive wall. But as it adds bricks, it is also shedding some, temporarily leaving gaps in its defences that allow the antibiotic to enter and kill it.
鈥淭he antibiotics are a bit like a crowbar that helps these bricks come out of the wall,鈥� says Edwards. 鈥淭he outer membrane doesn鈥檛 disintegrate; it doesn鈥檛 fall off. But there are clearly gaps where the antibiotic can then get to the second membrane.鈥�
He and his colleagues also uncovered why the antibiotic doesn鈥檛 always work: it only affected bacteria that were active and growing. When bacteria were dormant, a state they can enter to survive environmental stress such as nutrient deprivation, the polymyxin B was ineffective, because it wasn鈥檛 producing its armour.
However, the researchers found that providing sugar to the E. coli cells woke them from this dormant state and, within 15 minutes, armour production resumed and the cells were killed. The same is expected to apply to the other polymyxin antibiotic used therapeutically, polymyxin E.
Edwards says it might be possible to target dormant bacteria by giving people sugars, but there are dangers to waking these pathogens from their dormant state. 鈥淵ou don鈥檛 necessarily want bacteria at an infection site to start multiplying rapidly because that has its own downsides,鈥� he says. Instead, he adds, it might be possible to combine different drugs to bypass the hibernation state without waking the bacteria up.
Nature Microbiology
