My Enemy's Enemy: The challenge of antibiotic-resistant bacteria

The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of the University of Birmingham

“Antibiotic-resistant strains of bacteria represent a significant healthcare burden, and projections are grim as we face what has been termed “a return to the pre-antibiotic era”. Alongside infection, the growth of undesirable bacteria presents problems to farming, agriculture, food spoilage and industry.”  
- Dr Andrew Lovering

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Antibiotic-resistant strains of bacteria represent a significant healthcare burden, and projections are grim as we face what has been termed “a return to the pre-antibiotic era”. Alongside infection, the growth of undesirable bacteria presents problems to farming, agriculture, food spoilage and industry. Our traditional focus on drug regimens to clear bacteria has resulted in antibiotic resistance, but what if we could take a lesson from nature in how to kill them?

Historically, attempts have been made to isolate bacteriophages (viruses specific to bacteria) from the environment and apply these against infection. There are two major issues with this approach, firstly bacteriophage action is usually limited to a single type of bacteria, i.e. these are not broad-spectrum cure-alls, and secondly the bacteria can escape killing via mutation, much like they do when challenged with traditional antibiotics. There is however, another potential option to consider.  In the early 1960s, whilst attempting to recover a bacteriophage, Stolp & Starr discovered that the bacterial cells were actually being eaten by another, much smaller bacterium. This agent was christened Bdellovibrio bacteriovorus – bdello=leech; bacteriovorus=bacteria-eater. Further bacterial predators have been discovered since, but a fascination remains with this particular sub-type that burrows inside the prey cell and consumes it from within, before bursting out to begin the hunt anew.

What barriers would exist to clinical usage of Bdellovibrio? Firstly, bacterial-specificity is required and in all published material, this predator has never been observed to kill non-bacterial cells. Beyond this, the infected host/patient would have to tolerate the presence of the predator; there would have to be a significant “residency” of Bdellovibrio (where it can persist for a significant amount of time before it is cleared from the body). Additionally, experiments monitoring predation have been chiefly carried out in the lab, raising the question of whether the predator retains its killing rate when in a biotic (e.g. tissue/bloodstream/body cavity) environment. Recently, some progress has been made toward this goal via a revolutionary study involving the laboratories of Professor Liz Sockett at Nottingham, and Serge Mostowy at Imperial, wherein they injected Bdellovibrio into zebrafish larvae (an excellent transparent model system for monitoring infection). There were three promising observations from this pioneering approach:

1) Bdellovibrio cells persisted for 24-hours without any ill effects on the fish larvae

2) The predator was able to locate and kill the pathogen Shigella when both were present in the fish

3) This killing of Shigella was at therapeutic levels and (importantly) worked synergistically with the natural immune response.

This success in a whole animal model (and careful “accountancy” of checking predator and prey populations throughout) is a first in the field, resulting from a significant investment by the US Defence Research Agency, DARPA, to stimulate proof-of-principle research. There is beauty in the fact that, unlike conventional antibiotic treatment, predators tackle “superbugs” with the same voracity as susceptible bacteria – i.e. the resistance genes that protect pathogens against drugs are completely ineffectual against Bdellovibrio (which evolution has shaped to be able to attack bacteria in a multitude of ways).

One can imagine that it may be first easiest and safest to use any potential predator-therapy on external sites of infection, such as gum disease, wounds or diabetic foot ulcers. But there may eventually be scope for using Bdellovibrio (or even a genetically-modified variant) for other medical applications.

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