The Virus that Cures

The following documentary, entitled The Virus that Cures, was produced in 1997 by the BBC for the Horizon series. The 49-minute video illustrates some aspects related to phage therapy, or the use of bacteriophages (i.e., bacterial viruses) to treat bacterial infections. Phage therapy was practiced in the Soviet Union and it is still in use in some countries such as Georgia. The video allows us to listen to researchers from the Institute of Bacteriophage at Tbilisi, Georgia (full name: George Eliava Institute of Bacteriophage, Microbiology and Virology). It is frustrating to see that this technology is still awaiting a definite approval, or disapproval, by Western scientists and health regulatory agencies. Let's see if the (few) ongoing clinical trials will settle the question and, hopefully, powerful phage therapies will soon arrive to help fight antibiotic-resistant bacteria.



A collection of links related to phage therapy:

• Phage therapy, Wikipedia.
• Viruses vs. Superbugs, excellent site created for a science book on phage therapy. The site contains several pages with up-to-date information, including related literature, commented links, and news on phage therapy.
• George Eliava Institute of Bacteriophage, Microbiology and Virology, Georgian Academy of Sciences.
• Amazing Phage, a site containing many links and information on phage therapy, including a report on The Health Value of Bacteriophages.
• Treating Alzheimer's - through the nose, Israel21c (Sept. 2007). Treating Alzheimer with phages?
• Viruses Versus Bacteria, Sciencebase (Jan. 2007).
• Fighting bacterial infections with viruses, SciScoop (May 2006).
• Stalin's Forgotten Cure, Science (Oct. 2002). Full text available at Stalin's Forgotten Cure, Phage International.
• Viruses that slay bacteria draw new interest, Science News (June 2000).

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Antibiotics and viruses: a natural alliance?

At the right concentration, an antibiotic may be effective enough to kill a microbe, or at least to stop its growth. But lower antibiotic concentrations may have subtler effects on microorganisms. For instance, some bacteria respond in a funny way to very low, sub-lethal amounts of those antibiotics inhibiting cell division (such as penicillins): instead of dividing, cells become longer and longer, forming filaments. In this situation, cells are stressed but alive and still growing. Now, researchers from Université Paul Sabatier-Toulouse, France, have noticed that bacterial viruses (or phages) have also adapted to these circumstances.

When infected by these viruses, filamenting cells produce more offspring phages than the "healthier" cells do. The increased production of phages seems to be the result of faster lysis (due to defects on cell wall caused by the antibiotic) and a higher phage assembly. From the point of view of a phage making its living off bacteria, filamenting cells might be a warning sign: "hey, watch out, something is going wrong, the cells may die soon, so we better sack the place while we can."

The discovery of this phenomenon (where serendipity played a part) may have implications for medicine and biotechnology. For instance, the use of a combination of antibiotics and phages might be a new effective treatment for some bacterial infections. But the findings also bring out a possible, unexpected relationship between antibiotics and phages in the natural environment. It suggests that phages may work as amplifiers of the deadly effects of antibiotics, which are naturally produced by microorganisms such as actinomycetes. Both the phage and the antibiotic producer get some benefit: the former gets an extra burst from its unhealthy, filamenting host; while the latter gets rid of bacterial rivals in the neighborhood. Here, the antibiotic- and phage-sensitive bacteria get the worst part. But it's a cruel world.

Citation:
Comeau, A.M., Tétart, F., Trojet, S.N., Prère, M., Krisch, H.M., Fox, D. (2007). Phage-Antibiotic Synergy (PAS): β-Lactam and Quinolone Antibiotics Stimulate Virulent Phage Growth. PLoS ONE, 2(8), e799. DOI: 10.1371/journal.pone.0000799

Image: The PAS effect of phage ΦMFP on Escherichia coli MFP. Disks containing the β-lactam antibiotics (indicated by “+” symbols) produced large phage plaques in their proximity.

On Sept. 19, I added the following comment at the article site:

In addition to the potential implications for medicine (i.e., antibiotics+phages combination therapy), I like the thought-provoking idea of a possible co-evolution of certain traits in antibiotic-producing microbes and in phages infecting antibiotic-sensitive bacteria. One can imagine (have a look at Figure 1) several concentric, inhibition zones surrounding the cells (or mycelia) of an antibiotic producer. Inner zones, where antibiotic concentration is deadly for different microbes (depending on their respective sensitivities). And outer zones, where the antibiotic concentration is only sub-lethal but stimulate phage production in sensitive phage-microbe couples; we might picture it as a "defensive barrier" consisting of a higher local concentration of phages, ready to attack sensitive newcomers. Given that we really don't know the antibiotic concentrations that are actually produced by microorganisms in natural environments (at least I don't know), the sub-lethal effects of secondary metabolites may be more significant than their "antibiotic" effects. Just let your imagination fly...

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Viruses help to culture "the unculturable"

You probably know it: less than 1% of bacteria from environmental samples can be cultured in the laboratory; so, the 99% silent majority is called the "unculturable bacteria". But let's make it clear: "unculturable" only means that we haven't found a way to grow them yet.

The word "unculturable" is impressive and widely used, although perhaps misleading, and might be replaced by "yet to be cultured", "uncultured" or "uncultivated". Why are most microorganisms so fastidious, not growing in common media? Possible reasons: a required nutrient or "growth factor" is missing (perhaps produced in the natural environment by other bacteria), a component of the medium is toxic, or other bacteria in the sample produce an inhibitory substance.

One obvious method of eliminating common microorganisms of a complex sample is by the addition of antibiotics to the culture media. Hence, for the isolation of actinomycetes, cycloheximide and nalidixic acid can be used to inhibit the growth of fungi and Gram-negative bacteria, respectively. But additional removal of unwanted bacteria can get much more precise, thanks to phages (or bacteriophages, i.e. bacterial viruses). As a neat example, see a recent article that reports on the use of phages for the isolation of novel actinomycetes from termite guts. The authors utilized four sets of phages, which selectively targeted various groups of bacteria. The first set was specific for bacteria commonly culturable from termite guts: Bacillus, Enterococcus, Staphylococcus, Lactococcus, Paenibacillus. The other three groups of phages were specifically directed against actinomycetes of the genera Streptomyces, Micromonospora and Nocardia/Rhodococcus, respectively. By sequentially using the sets of phages, the researchers were able to uncover and grow a number of new actinomycetes, which could not be identified without the phage treatment.

Culture-independent techniques such as metagenomics are a centre of attention, as they are providing a wealth of information from uncultured microorganisms. But efforts directed to "culturing the unculturable" are still needed for a better understanding of the microbial universe, don't you think so?

Reference:
Kurtböke, D., French, J. (2007). Use of phage battery to investigate the actinofloral layers of termite gut microflora. Journal of Applied Microbiology, 103(3), 722-734. DOI: 10.1111/j.1365-2672.2007.03308.x

Image credits:
Electron micrographs of a bacteriophage (phi HAU3) negatively stained with uranyl acetate. Reproduced from: Zhou X, Deng Z, Hopwood DA, Kieser T. Characterization of phi HAU3, a broad-host-range temperate Streptomyces phage, and development of phasmids. J. Bacteriol. (1994) 176, 2096-2099. Copyright 1994, American Society for Microbiology.

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Size and shape in the genomes of actinomycetes

A new genome sequence of an antibiotic-producing actinomycete has been recently published in Nature Biotechnology. This seems to me a good excuse to highlight some peculiar aspects of genome evolution in this group of bacteria.

The mentioned microorganism is Saccharopolyspora erythraea, known as an industrial source for erythromycin. The size of the genome, 8.2 Mbp (Mbp = megabasepairs = million base pairs), is similar to that of Streptomyces coelicolor (8.7 Mbp) and Streptomyces avermitilis (9 Mbp). These are some of the largest genomes in bacteria, although much smaller genomes are found in other actinomycetes. An example of the latter is Bifidobacterium adolescentis, with only 2.1 Mbp (not to mention the obligate parasite Tropheryma whipplei, the causative agent of Whipple's disease, with a tiny 0.9-Mbp genome).

In the Sac. erythraea chromosome, the majority of conserved, essential genes are contained in a region extending either side of the origin of replication (the "core"). This genome organization consisting of core and "non-core" regions is also found in streptomycetes. The non-core region (3.8 Mbp in Sac. erythraea) includes most of the genes coding for conditionally adaptive functions, such as production of secondary metabolites (although the genes for erythromycin synthesis happen to be located in the core).

What about shape? Most bacteria possess a circular chromosome, which is the case of Sac. erythraea and the majority of actinomycetes. On the other hand, at least some species of Streptomyces and Rhodococcus contain linear chromosomes. Given that actinomycetes more closely related to Rhodococcus (such as Nocardia) possess circular chromosomes, linearization may have occurred more than once during the evolution of this group of bacteria. Remarkably, genomic instability is frequently found in Streptomyces: the non-core region of the chromosome contains transposable elements and is prone to undergo rearrangements and deletions. This leads to large-scale variations, even among genomes of the same species. When the telomeres are lost, a circular chromosome results, and there are examples of the co-existence of linear and circular forms for a particular strain. It has been proposed that linear chromosomes arose from the recombination of linear plasmids with circular chromosomes, and that linear plasmids evolved from bacteriophages.

(Figure: Schematic representation of Saccharopolyspora erythraea chromosome. Reprinted by permission from Macmillan Publishers Ltd: Nat. Biotechnol. 25: 447-453, copyright 2007).

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