The Craigslist of Antibiotic Resistance
(Before we get going: this the the 100th post on Byte Size Biology. Happy Birthday to me!)
Resistance to antibiotics is a huge clinical problem. In the US, more people die of methicillin-resistant Staphylococcus aureus (MRSA) infections (nearly 19,000 in 2006) than of AIDS (14,627). We know that antibiotic resistance is carried on mobile genetic elements between bacterial species in lateral gene transfer events. In fact, most of the MRSA’s resistance genes are traceable to other species. It is as if MRSA made some great choices when purchasing antibiotic resistance in the bacterial community market, and now it is one tough bug that is heavily armored and very hard to mess with.
How common then are antibiotic resistance genes? Very. But a recent article in Science from George Church’s group in Harvard Medical School shows us just how common and diverse those genes are. They analyzed 572 bacterial strains from the stool and saliva of two healthy persons who have not taken antibiotics for at least one year. They also analyzed metagenomic sequences, obtained directly from the samples without culturing them first. Many of the benign bacteria had antibiotic resistance genes similar to those found in pathogenic (disease causing) bacteria. But the real kicker is that most of the antibiotic genes isolated — in the metagenomic samples — were evolutionarily distant from the currently known antibiotic resistance genes. The researchers checked the products of those distantly related genes for functionality, and found that despite a rather low similarity to known resistance gene products (50-60% identity in the amino acid sequence, and sometimes as low as 35%) the genes conferred antibiotic resistance when expressed in E. coli: a normally non-resistant bacterial strain. So the diversity of evolutionary related resistance genes is much larger than we thought. It is like being a child who grew up in a cookie-cutter suburb, who upon his first visit to the city finds out that there are many other types of houses and buildings people live and work in.
Church & co. have discovered three interesting things. First, that there is a broad evolutionary spectrum of antibiotic resistance genes. Until now, we have only known of a very biased sample of those genes, namely those that were sequenced in known human pathogens. But there is a huge evolutionary reservoir out there. This reservoir is sitting in normally benign gut bacteria, and even this work has only scratched the surface of how extensive this reservoir is.
Second, these new resistance genes may not transfer well to human pathogens. They conclude this because since those genes were not found in human pathogens. However, absence of proof is not proof of absence: the new, low similarity genes may still exist in serovars (specific bacterial strains) that were never sequenced, we do not know for sure they are absent in pathogens. But having not found them before in pathogens, and having found them now in non-pathogens, strongly suggests there is some sort of barrier that limits transfer between certain species, and indeed between non-pathogens to pathogens. If indeed there is such a barrier, we still don’t know what it is.
Third, among the new resistance genes, some had very low sequence similarity (as low as 35% protein sequence identity). Usually at such low identity percentages, the functions of the proteins are different. But in this case, they found a high conservation of function. This is interesting, since it shows that the resistance proteins evolve widely, yet their functionality is robustly conserved.
This is not the first time this group has made a surprising discovery about antibiotic resistance. Last year they have shown that many soil bacteria are not only resistant to antibiotics, but actually eat them for lunch: antibiotics as a food source.
In their most recent article, Sommer, Dantas and Church have hit upon the craigslist for antibiotic resistance used by bacteria living in the human body. The basic genomic material needed for antibiotic resistance is readily available at your local bacterial community. Resistance genes are everywhere, and it is clear that, despite transmission barriers between species, they are transmitted. Bacteria have a large pool form which to draw new resistance genes. The arms race between drug developers and bacteria just got this much tougher.
One small gripe: this article uses “low homology” and “high homology”. Arrrgghh….
Finally, speaking of craigslist…
Sommer, M., Dantas, G., & Church, G. (2009). Functional Characterization of the Antibiotic Resistance Reservoir in the Human Microflora Science, 325 (5944), 1128-1131 DOI: 10.1126/science.1176950
Dantas, G., Sommer, M., Oluwasegun, R., & Church, G. (2008). Bacteria Subsisting on Antibiotics Science, 320 (5872), 100-103 DOI: 10.1126/science.1155157