Thursday, November 13, 2008

Utilizing Natural Killers: Phage-Based Antimicrobials

ResearchBlogging.orgMy last article on the origins of antibiotic resistance perked my interest in the current thinking of how we scientists are planning on overcoming this challange. The two answers that most people will consider are 1) develop new chemical analogs of current antibiotic compounds, and 2) discover novel compounds that act as antimicrobials.

It is this second concept that appeals most to me. However, it raises the question, "WLike this cruise missile, bacteriophages could provide highly targeted attacks against our (bacterial) do we look for novel antimicrobial compounds?"

Some are taking a step back to the days of Felming and looking everywhere: fungal isolates, plant extracts, bacterial products, etc. However, we can not forget the natural-born killers of bacteria. . . thier phages.

Bacteriophages have been coevolving with thier hosts since the dawn of time. As such, I would imagine they know a thing or two about killing a bacterial cell. Phage proteins interact with those of their host to modify and shutdown various functions. By taping into these types of interactions, we could exploit phage proteins to develop ways to attack the host. Furthermore, with the number and diversity of the phage world, there is great potential that each phage attacks the host in a slightly different fashion.

So now the question becomes, how do we find which proteins of the bacteriophage which function as bacteriocidal or bacteriostatic molecules?

The screen is relatively simple. Ask which phage genes, when inducibly expressed in the host, kill the host cell. Researchers have already performed this type of assay in Staphylococcus, and more recently, in the Mycobacteria.

Utilizing an acetimide-inducible promoter system, 3 phage genes (from temperate mycobacteriophage L5) were discovered to have toxic effects on the host, Mycobacterium smegmatis. Further characterization of these genes can find the specific host targets on which they act. Subsequently, small molecules could be developed and screened to act in the same location.

This method could allow the discovery of new drug targets and the drugs which access them. It is fast assay that uses phages in a clever and indirect way to fight disease.

1) Liu et al. (2004). "Antimicrobial drug discovery through bacteriophage genomics". Nat Biotechnol 22, 185-191.

2)Rybniker, J., Plum, G., Robinson, N., Small, P., & Hartmann, P. (2008). Identification of three cytotoxic early proteins of mycobacteriophage L5 leading to growth inhibition in Mycobacterium smegmatis Microbiology, 154 (8), 2304-2314 DOI: 10.1099/mic.0.2008/017004-0p>

Other articles of interest
The Origins of Antibiotic Resistance
I'll Have My Bacteria Extra-CRISPR