Targeting antibiotics…

rb1INHERITANCE, the process by which some of your parents DNA is repackaged in the agreeable form of you, can be described as ‘vertical gene transfer’, i.e. the passage of information down a lineage. However, this is not the only means by which DNA information can travel.

I once spent six years conducting research into the mechanisms by which resistance to antibiotics can be spread within, and between, bacterial species. Much of this focussed on horizontal gene transfer (HGT), specifically the transfer between bacteria of DNA packages called ‘plasmids’, which can contain a full set of instructions on how to resist an antibiotic. Unlike inheritance, HGT is more akin to you reaching out and placing your hand on your cousin and acquiring their ginger hair, or nose shape.

This is of course a very serious issue, in fact it has never been more serious. The subject of HGT is a key topic in many aspects of biological sciences, and I’ve blogged about some of the interesting aspects of such DNA information transfer before.

In the past 10 years or so, an oft’ discussed topic of conversation at the scientific conferences I’ve attended has been the development of targeted antimicrobials. This is a move towards being able to ‘take-out’ (in the mafia sense) those specific bacterial species that are causing a particular infection/disease, but without providing a selective pressure to develop resistance to the drug on this, and neighbouring, bacterial species.

Broadly speaking, there have been two major lines of research that have resulted from such discussions:

  • Anti-virulence factors, where drugs are employed not to kill the bacteria, but instead to make them more benign, to ‘clip their claws’, so to speak.
  • Targeted antibiotics, where only the specific micro-organism causing the problem is killed.

The rationale for the first line of research is that forcing bacteria to choose between life and death is a strong selective pressure, which inevitably results in strong selection for a bacterial cells that are resistant, and survive. However, if you target the specific weapons a bacterium uses to invade new territory (which are what cause the damage to us), then you simple force them into a choice between aggressively invading new territory, or living a manageable subsistence existence; thus a the selective pressure is weaker, they get to survive as long as they play ball. Ultimately they may be removed by the immune system in any case.

The second line of research is concerned with the fact that most pharmaceutical companies would prefer to develop a ‘one hit wonder’ drug that can be used against a broad range of bacteria, but if you have an infection caused by a particular species, it is not best practise to kill every other bacteria species in the vicinity. This needlessly breeds resistance in species of bacteria that are otherwise harmlessly occupying your skin, resulting in a reservoir of . The problem has been finding a balance between too narrow and activity and too broad.

Today’s research blog is an example of a targeted antibiotic.

In the January 2009 issue of the International Journal of Antimicrobial Agents, Michael Franzman, (Doctor of Dental Surgery), described an antimicrobial peptide (SMAP28) that has been targeted to a bacterium, Porphyromonas gingivalis, which is known to cause gum disease. Antimicrobial peptides are a class of antimicrobial agents that form part of the innate (natural barrier) defence system, and are produced by just about every class of life you’d care to mention, from single-celled fungi to humans. They’re cheap and easy to produce, have few side-effects, unlike typical antibiotics, but can be used alongside other antibiotics.

[Interestingly, in an aside, I was once head-hunted for a PhD studentship to look at human hair-follicle antimicrobial peptides. It had been hypothesised that one of the reasons that humans still have so many hair follicles (small spherical group of cells containing a cavity), regardless of whether they still produce an actual hair, is because they produce antimicrobial peptides that are essential for controlling the numbers and types of bacterial on your skin, keeping you free of infection.]

In the current paper, they raised an antibody (those proteins in your blood that recognise foreign bodies and target them for destruction by your immune system) that targets the outer surface of their target bacterium, Porphyromonas gingivalis (P. gingivalis); they then joined these antibodies to their antimicrobial peptide. The aim being that you can use a lower concentration of your antimicrobial, because each of these molecules will now stick to the target, rather than spread out randomly. This is not the first time this technology has been employed; a similar approach has been used to protect plants from a specific bacterial infection, and likewise the approach has been successful against the superbug MRSA, whilst not killing related, harmless, bacteria.

Now, the antimicrobial peptide they’re using in this study is a broad-spectrum antibiotic, and has been shown to effectively inhibit numerous bacterial species found in the mouth, however this includes the good as well as the bad. Reduction of the helpful ‘good’ bacteria can leave your body open to infection by opportunistic resistant bacteria. So the aims are two-fold:

  • To target an effective antimicrobial peptide against a causative organism of gum disease
  • To achieve this activity at a low concentration of antimicrobial peptide, thus reducing any possible side-effects.

They performed the appropriate controls, which included finding out whether the antibody on its own has any effect on the growth of the targeted bacterium. It doesn’t.

Also, as they had to chemically modify the antimicrobial peptide to make it possible to join it to the antibody, they checked to make sure that the chemically modified antimicrobial still has its activity. It does.

In their experiment, they don’t use an animal or human model; instead they use an artificially generated microbial community containing four known gum-dwelling bacteria. They found that at half the concentration required to kill all of the bacteria in their community, they were able to kill just their target bacterium P. gingivalis.

It is still early days in this type of result, which they admit. They still have a lot to learn about the nature of the joined antibody-antimicrobial peptide, as they did not some variability in its activity; this would need to be more consistent and predictable. They are also not limited to using antibodies, they could use other proteins that are known to be specific to a target bacterium. They don’t list an extensive range of alternatives besides this; I could suggest several highly effective approaches I would take myself, but then I do work in a lab with a particular expertise for molecular delivery/targeting vehicles.

What is important is the principle and the direction of such research. A means to target specific disease-causing bacteria without harming the normal, healthy ‘good’ bacteria.

FRANZMAN, M., BURNELL, K., DEHKORDIVAKIL, F., GUTHMILLER, J., DAWSON, D., & BROGDEN, K. (2009). Targeted antimicrobial activity of a specific IgG–SMAP28 conjugate against Porphyromonas gingivalis in a mixed culture International Journal of Antimicrobial Agents, 33 (1), 14-20 DOI: 10.1016/j.ijantimicag.2008.05.021


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