Bacterial Arms Race?


As bacteria continually develop resistance to antibiotics, tactics to combat infection need to change. One option is using the weapons bacteria themselves use to survive, writes James Kelly.

With antibiotic resistance on the rise, in part due to our own heavy-handedness and also due to newer and deadlier strains of bacteria and viruses emerging at a worrying rate, we are in dire need of something new. Bacterial suicide bombers and tiny needle-armed assailants may just be that something. Ongoing investigation of the nanoscopic arsenals employed by bacteria, in their struggle for survival in the micro and macroscopic worlds, is yielding some interesting results that might help humans defend against the ever-more threatening microscopic world.

In 1954, while working at the Pasteur Institute in Paris, biologist François Jacob made an unusual discovery. Jacob was studying Pseudomonas aeruginosa, a bacterium that even today kills many people in hospitals, when he noticed that one strain of P. aeruginosa was releasing a substance that killed other strains of the same species. This was an astonishing level of specificity, given that most modern antibiotics kill a wide range of species, not just particular strains. Later studies showed that the substance, named pyocin, was far larger than most other toxins released by bacteria. Electron microscopy revealed another unusual thing about pyocin – its shape. It resembled a rocket, having a tubular body with several fibres protruding from one end.

While it may look like a rocket, it acts more like a floating drill. Housed inside the tubular body is a second, narrower tube. When the fibres attach to a bacterium, the tubular body contracts, propelling the second tube through the bacterium’s protective outer layers. This action quickly kills the target, leaving surrounding non-target cells unharmed. This level of efficiency isn’t unique to P. aeruginosa, with a variety of bacteria producing similar weaponry. Some bacteria, such as Serratia entomophilia, even use it to take down bigger targets. S. entomophilia uses its ‘drill’ particles to attack the New Zealand grass grub, a beetle larvae. Crucially, S. entomophilia doesn’t just stab the larvae; it uses its machinery to deliver a toxin that apparently stops the larvae eating. The weakened larvae are then susceptible to invasion by S. entomophilia, which feasts on the larvae’s internal tissues once inside.

There is a downside to utilising such deadly tools. The components of these drill particles are synthesised and assembled intracellularly, and the end product is too large to export safely; their release requires going kamikaze. But what’s the point in such a pyrrhic victory? The simple answer is species survival. Species, or even strains, in which some individuals are likely to sacrifice themselves ‘for the greater good’ must have been more successful than those where they aren’t.

Some bacteria have, for whatever evolutionary reasons, avoided the necessity of self-sacrifice. One such bacterium is Photorhadus luminescens, which may have been responsible for glowing wounds observed during the American Civil War. P. luminescens is found in the gut of some worms, and is released when the worms burrow into an insect (or host). Genetic studies of P. luminescens have identified the presence of all the necessary genes for a drill particle. As lysis (cell bursting) of P. luminescens in conjunction with target infection has not been observed, it is thought that the bacterium must have some mechanism for exporting the drill components before assembly. The drill particle, along with several toxins and virulence factors, sets about liquefying the insect and destroying any potential competition. Studies carried out using wax moth larvae indicate that invasion by P. luminescens is lethal, with all the larvae dying within minutes.

Another, somewhat cruder way in which some bacteria have avoided the suicide mission is to arm themselves with spikes. Similar in structure to the drill particles, though lacking end fibres, these spikes stick out of the cell wall and stab other cells that the bacterium comes in contact with. Some bacteria have poison-tipped spikes, while others use the spikes as a means to inject toxins into target cells. They can even kill mammalian cells, which are several times larger. A relative of the cholera bacterium has been observed killing amoebas and mouse cells in this manner. The spikes are known as type VI secretion systems.

The advantages of possessing such appendages in the constant struggle for survival are obvious, but what exactly is their origin? The pyocins bare a striking resemblance to bacteriophages (viruses that attack bacteria). Bacteriophages consist of a head/capsule, attached to a tube with grabbing fibres at the opposite end. The fibres attach to specific bacteria, the cell wall is penetrated, and the genetic material contained in the capsule is injected into the bacteria. The genetic material then incorporates itself into the host genome, turning the bacterium into a bacteriophage factory. In most cases the release of the produced bacteriophages occurs through lysis of the bacterium. The R-type pyocin discovered by François Jacob looks just like a bacteriophage without a capsule, and the type VI secretion system looks like one without a capsule or fibres. In fact, the resemblance is so close that many biologists believe it is unlikely that these structures evolved independently. One possibility is that the genes’ coding for the various components of bacteriophages may have become incorporated into the bacterial genome without lysis occurring (perhaps due to some mutation), and that subsequent mutations then produced structures like R-type pyocin.

There are phages for most bacteria, so why not use them to fight harmful bacteria such as Salmonella and E. coli, or as pesticides? Their efficiency and specificity are far beyond most of the current options available. The problem is control. Bacteriophages change and evolve, and sometimes cause bacterial mutation instead of death. The mutation responsible for the E. coli strain that affected so many people in Germany last year was the result of injection by a phage. The use of specific phage components is a safer, more elegant way of achieving the same goals. Through the use of various techniques, scientists are creating hybrids between pyocins and phages, with the hope of producing defences against just about any bacterium.

However, our own adaptive immunity could prevent prolonged use of these hybrids, as they would most likely trigger an immune response. So the problem moves from control to avoidance. Producing an effective hybrid that the human body would not recognise as foreign is still way down the line. Some labs aren’t even considering the possibility, but instead trying to kill the bacteria before they get near us. Ecolab, a company based in Minnesota, is trying to produce an E.coli pyocin that can be applied to beef. Some have even suggested attempting to use the hybrids as nano-syringes for delivering drugs to cells. Another factor to consider is that bacteria can develop resistance to pyocins/secretion systems, just as they do to antibiotics. However, given the specificity and efficiency of pyocins/secretion systems, the adaptation process would take longer than antibiotic resistance does to develop.

While we are still some distance from our goals, the study of bacterial warfare is providing us with some novel ideas for our own struggle against them.