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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Intertwined lives: symbiosis

Some actinomycetes are known for establishing symbioses with other organisms. A typical example is the formation of nodules on the roots of certain plants by soil bacteria of the genus Frankia. Although these microbes can also be found as free forms in the soil, the nodule constitutes a comfortable home for Frankia, with abundance of carbon sources. Additionally, it's an adequate environment for an activity that greatly benefits the plant: nitrogen fixation. This is a process by which atmospheric nitrogen is converted into ammonia, nitrate and other compounds. Hence, the actinomycete fixes nitrogen and fertilizes its host plant. Recently, the genomes of three Frankia strains have been sequenced, which will help to understand how different strains are able to select and colonize certain plant hosts but not others.
(Image: Nodule from Alnus incana subsp. rugosa, about 1.5 cm diameter; D. R. Benson)

In other actinomycetal symbioses, the second partner is an insect, for instance a beewolf. Beewolves are not wolves, but a type of wasps that hunt honeybees to feed their larvae. After digging a nest in sandy soil, the female beewolf deposits an egg together with one or several paralyzed bees. But the underground nest is humid and warm, and the wasp larva may easily get infested by pathogenic microorganisms. As an strategy to diminish larva infestation, beewolves cultivate and use their own antibiotic-producing actinomycetes. Antennae of female beewolves have specialized glands housing symbiotic Streptomyces bacteria. The wasp applies a secretion from these glands all over the nest before leaving its egg. Later, the larva takes the bacteria and applies them to its cocoon, resulting in lower risk of fungal infestation. Sequencing DNA from both symbiotic partners is beginning to yield interesting results.
(Image: Philanthus triangulum, a European beewolf)

But the story can get more complicated. Imagine a symbiosis with four co-evolving partners: three of them are engaged in a mutualistic relationship, while the fourth one is a parasite. That's the beautiful case of fungus-growing ants. In their underground nests, the ants grow a mushroom-like fungus by feeding it with plant materials or other organic matter. In turn, the fungus serves as food for the ants (yes, this is agriculture!). But every garden has its pests, and the ants' farm is home for the Escovopsis mold. Escovopsis is a specialized pest, found only on the crop of farming ants. To battle the parasite, the ants combine special behaviors and microbial symbionts. These insects carry a bunch of antibiotic-producing actinomycetes in elaborate cuticular crypts, supported by unique exocrine glands. The symbiotic bacteria produce substances that specifically inhibit Escovopsis growth. Although initially identified as Streptomyces, the actinomycete symbionts appear to belong to the Pseudonocardia genus. The case of the fungus-growing ants has become a textbook example for teaching evolution and symbiosis (educational materials are available from the University of Nebraska State Museum or from the PBS Evolution project)
(Image by Grey Wulf: leaf-cutter ants [a type of fungus-growing ants])

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