Pirating Survival

Antibiotics have always seemed a universally effective answer to bacterial infections. Recent studies are showing however, that this is not necessarily the case, as many bacterial species have developed ways to combat antibiotic action. In particular, Escherichia coli uses a compound called indole to communicate between bacterial cells, augmenting antibiotic tolerance. This compound triggers the oxidative stress response and phage shock response pathways in the bacteria, which protect against varying types of oxidative action. This leads to an increase in so-called “persisters,” those bacteria which survive antibiotic exposure without a genetic basis for survival (such as DNA vectors which confer specific antibiotic resistance).

Where things get interesting is in the interspecies interaction these communications can facilitate. Researchers out of Boston have found that another bacteria, Salmonella typhimurium is able to piggyback on that signal, and improve its own chances of survival in response to indole. The nifty part is that S. typhimurium doesn’t produce indole itself, and so this isn’t an incidental, interspecies cross-communication. Instead it appears to be more like bacterial wire-tapping.

There are some differences in the bacterial response to indole between E. coli and S. typhimurium, but by and large it seems clear that both have developed a signaling system based around indole that increases cellular defenses. The largest difference is that S. typhimurium is “listening in” on E. coli communications on when to beef up defense. How do these cellular mechanisms function, you ask? Well…

The states which indole triggers in both bacteria, the oxidative stress response and phage shock response, are both reactions to destruction of the bacterial cell membrane. Normally, the oxidative stress response is triggered by free oxidizing agents, often what are called reactive oxygen species which are part of the human immune response. These forms of oxygen (such as hydroxyl or superoxide radicals) are much more capable of oxidizing (removing electrons from) other molecules compared to molecular oxygen (O­2). These can then damage or degrade a wide variety of biological molecules (such as DNA, RNA, proteins, and cellular membranes). You know all those antioxidants foods are always bragging about having? Well, they help to neutralize these types of compounds, which in turn protects your cells from serious oxidative damage. Activation of the oxidative stress response triggers transcription of genes which code for enzymes that repair damage caused by oxidation. In this context, the process serves to maintain the integrity of the bacterial cell membrane.

In much the same way, phage shock response combats the membrane damage that phagocytes (cells that eat other cells) cause. Phagocytes are an integral part of the human immune response and breaking down bacterial membranes is one of the primary steps of bacterial killing. By negating this process via phage shock response, bacteria can evade the human body’s defenses. Without the ability to degrade cellular membranes, the immune cells cannot attack other, intracellular bacterial components. (Note that both of these explanations are gross simplifications, and the processes are much more complex and dynamic in actuality. For our purposes though, this should do.)

So how does this relate to antibiotic resistance? Well antibiotics typically attack via oxidation of the cell membrane and internal structures. By triggering these responses, indole signaling allows these bacteria to enhance survival when antibiotics are used. When plated with antibiotics (in the study, they used carbenicillin and ciprofloxacin), bacterial survival was increased in both indole-treated E. coli and indole-treated S. typhimurium. The fact that S. typhimurium is able to react to indole produced by E. coli without its own native indole production suggests a remarkable co-evolution of survival mechanisms. It also gives the distinct impression that bacteria are slowly beginning to organize their efforts of killing us, which seems, at the very least, ominous.

Original article: http://www.pnas.org/content/110/35/14420.abstract

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