Destroying Bacterial Cell Walls May End Antibiotic Resistance Forever

A new method for cutting off building supplies to resistance-enabling outer membranes.

Image: gram-negative citrobacter koseri/Nathan Reading

Bacteria become drug-resistant and thereby highly dangerous in large part because they develop an extra wall. It's as simple as that: A lipid-based outer membrane in "gram-negative" bacteria prevents infiltration by conventional antibiotic drugs and natural immune system responses. Absent countermeasures, the bacteria turn fully virulent and run wild. Bad things happen, up to and including death. Toppling or penetrating this wall has thus been one of a few key fronts in the microbial arms race. 

The wall found in gram-negative bacteria is actually a second membrane, composed of large molecules called lipopolysaccharides (LPS). LPS, as both an endotoxin and pyrotoxin, is bad for a whole range of reasons, spiking fevers by turning the body's natural thermostat up while generally wreaking immune system havoc, boosting inflammatory measures to the point that the host is effectively self-destructing. Once LPS molecules reach a critical mass within the human body—which is far more susceptible to this kind of attack than other animals—septic shock results, with death not far behind. 

Note that all of the above is in addition to the LPS wall's role in keeping our defenses, natural and otherwise, at bay. Typically, diffusion of molecules across this membrane and into the bacterial guts, where said bacterium can be destroyed or rendered harmless, is mediated by tiny channels called porins. It's these porins that adapt in size to keep antibiotics or other threats on the outside. Gaining access through these ports has been a long-standing challenge in antibiotic development, but a study out this week in the journal Nature describes the "Achilles' heel" of this bacterial defensive strategy, a mechanism for not just killing bacteria off, but preventing the development of resistance in the first place. 

The success comes not from new ways to crash the gram-negative gateways or novel molecules designed to tear down the wall/outer membrane itself, but from preventing the development/reinforcement of the wall in the very first place. It might help to imagine a castle within some medieval (or Elder Scrolls) city. There is the city wall, but within that wall there is another wall, that of the castle itself. The way the outer wall functions is that it gets reinforcements (building materials, mostly) sent from the inner castle. Say these materials have to pass over a moat en route, utilizing a bridge. If you could take out the bridge, you would take out the wall too, and soon enough, the castle. 

"We have identified the path and gate used by the bacteria to transport the barrier building blocks to the outer surface," said research team leader Changjiang Dong in a statement. "Importantly, we have demonstrated that the bacteria would die if the gate is locked." 

More specifically, the researchers were able to finely map the the "barrel-like" structures that move LPS materials to the outer membrane, for the very first time.

"Seven LPS transport proteins form a trans-envelope protein complex responsible for the transport of LPS from the inner membrane to the outer membrane, the mechanism for which is poorly understood," the study reports. "LptE [one of the transport proteins] adopts a roll-like structure located inside the barrel of LptD to form an unprecedented two-protein 'barrel and plug' architecture," that allows membrane building materials out, but prevents drugs or damaging immune system agents from getting it. 

A final advantage of this method is that it really only attacks the wall, not the bacterium proper. According to the study's lead author Haohao Dong, this fact might lead to the treatment to finally end all treatments. "Because new drugs will not need to enter the bacteria itself," he said, "we hope that the bacteria will not be able to develop drug resistance in future."