Antibiotic Resistance in the Environment

WatchMojo has a nice video on historical predictions that turned out to be false. #3 is pretty interesting:

The time has come to close the book on infectious diseases.

Those words were spoken back in 1969 by the Surgeon General of the US. I don’t doubt that they were reflective of the microbiological zeitgeist back then– the virtual onslaught of penicillin against anything infectious was a thing of wonder.

Of course, this era was soon followed by one of resistance.

Antibiotic resistance: origin story

Our discussions of antibiotic resistance usually take place in clinical contexts, which is why it may come off as strange to know that antibiotic resistance genes had their origins in the environment. There are so many different lines of evidence substantiating this. Resistance genes to popular antibiotics are found in environmental as well as clinical strains (1). Significantly, antibiotic resistance genes have been isolated from environments which had no earthly exposure to anything clinical- including glacier environments (2) and a cave that has been isolated for over 4 million years (3). In addition to being found in remote environments, antibiotic resistance genes are also ancient. A letter to Nature reported finding a “highly diverse collection of genes encoding resistance to [antibiotics]” in “rigorously authenticated ancient DNA from 30,000-year-old Beringian permafrost sediments” (4). They also ran structural analyses of the ancient variant of a particular resistance gene, and found it to be similar to its modern variant.

The 30,000 year old Dawson Tephra yielded antibiotic resistance genes

This pretty effectively seals the debate: antibiotic resistance genes originated in the environment, well before humans started using commercialized antibiotics in clinical settings.

Why do bacteria need antibiotic resistance in the environment?

Part of the answer to that is simple. Environmental bacteria need antibiotic resistance for the precise reason they need it in clinical settings: protection against antibiotics. Antibiotics have important roles in bacterial ecology- bacteria can secrete them to fend off competition, low levels of antibiotics can modulate cell transcriptome (5), they act as signaling molecules for communication between bacterial cells, and so forth. Given the role antibiotics have to play in bacterial ecology, it’s not surprising bacteria would have defense mechanisms to protect themselves against higher concentrations of the stuff. Heck, antibiotics are even used as nutrients- a report documented the growth of a wide range of bacteria using antibiotics as their sole carbon source (6). Interestingly, these same genera would also have resistance mechanisms against the antibiotics at clinically relevant (i.e. harmful) levels.

This still doesn’t address some parts of the riddle. Antibiotic resistance genes are surprisingly widespread in nature- even found in the genomes of bacteria which don’t produce antibiotics. Consider the MDR efflux pump, a hallmark of a wide range of multi drug resistant bacteria. This is found in a lot of environmental bacteria, even those who don’t produce antibiotics.

This goes to the question of what even is an antibiotic resistance gene. As the name suggests, the efflux pump’s actions are rather general- it pumps things out of the cell, which may or may not include antibiotics. A shovel is perfectly capable of bashing people’s heads in, just that it’s not commonly used that way among people of high culture. Similarly, garden variety furniture in the bacterial cell can sometimes be conscripted for the service of antibiotic resistance. This is especially notable among opportunistic bacteria with large genomes who have genes to adapt to a whole host of different environments. They may, quite unintentionally, come packing with some metabolite-modifying enzymes which double as antibiotic resistance machinations. This blurs the definitional lines considerably- perhaps a shovel, divorced from its context, has no intrinsic form that defines its function. Fight me Aristotle.

Shift from environment to clinic

A clinically relevant case in point- Providential struartii has an enzyme to modify the bacterial peptidoglycan (2′-N-acetyltransferase) (1). Peptidoglycan is a component of the bacterial cell wall, as garden variety a molecule as they come. However, due to its similarity to the antibiotic compound gentamycin, our boy P. struartii unintentionally becomes equipped to deal with gentamycin in the environment as well.

Now consider some consequences down the line. In the context of a cell, every whir in every cog in the overarching metabolic network displays a finely tuned balance. This is because metabolic networks tend to be integrated systems, and change in one component (say the expression of an enzyme) may translate to a larger change in another. 2′-N-acetyltransferase is tightly regulated in the biochemical pathway in which it normally finds itself. But what if the gene is shipped off to another bacteria via a plasmid? There is no more biochemical context, much less fine-tuning. The enzyme is now constitutively expressed. In its new host, the enzyme classifies strictly as an antibiotic resistance mechanism. A shift (or stripping away) of context thus results in a functional upheaval as well. Indeed, certain antibiotic genes found on integrons come bundled with strong promoters.

This is a very basic example where a bacterial gene found in environmental strains that had nothing to do with antibiotic resistance becomes a resistance gene, triggered by an initial overlap in function. Not much was needed as modes of persuasion, just “shippability” via gene capture units and a consequent loss of regulatory context.

References

1. Martínez JL. Antibiotics and antibiotic resistance genes in natural environments. Science. 2008 Jul 18;321(5887):365–7.
2. Segawa T, Takeuchi N, Rivera A, Yamada A, Yoshimura Y, Barcaza G, Shinbori K, Motoyama H, Kohshima S, Ushida K. Distribution of antibiotic resistance genes in glacier environments. Environmental microbiology reports. 2013 Feb 1;5(1):127–34.
3. Bhullar K, Waglechner N, Pawlowski A, Koteva K, Banks ED, Johnston MD, Barton HA, Wright GD. Antibiotic resistance is prevalent in an isolated cave microbiome. PloS one. 2012 Apr 11;7(4):e34953.
4. D’Costa VM, King CE, Kalan L, Morar M, Sung WW, Schwarz C, Froese D, Zazula G, Calmels F, Debruyne R, Golding GB. Antibiotic resistance is ancient. Nature. 2011 Sep 22;477(7365):457–61.
5. Fajardo A, Martínez JL. Antibiotics as signals that trigger specific bacterial responses. Current opinion in microbiology. 2008 Apr 30;11(2):161–7.
6. Dantas G, Sommer MO, Oluwasegun RD, Church GM. Bacteria subsisting on antibiotics. Science. 2008 Apr 4;320(5872):100–3.