Francesca Tomasi received her B.A. from the University of Chicago and is now a microbiologist.
In 1928, Alexander Fleming stumbled upon the mold that changed the world: penicillin, the first antibiotic, would forever change the course of medicine. Infections that once killed millions of people and kept the average human life expectancy near 50 were cured almost overnight. In 1967, William H. Stewart, the US Surgeon General, told the White House “It’s time to close the books on infectious diseases, declare the war against pestilence won, and shift natural resources to such chronic problems as cancer and heart disease.” It was a medical fairy tale. But now there’s a sequel.
We are on the brink of a post-antibiotic era. You’ve heard it before, and you’ll hear it again. The over-prescription and misuse of antimicrobial drugs over the last nine decades created the perfect environment for bacteria to become resistant to most first-line, many second-line and even some third-line antibiotics. In fact, some diseases now can only be treated using the latter category of drugs. These are the more powerful, more toxic drugs that were only supposed to be around as a last resort. Alexander Fleming warned us about it in his Nobel Prize acceptance speech: "The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant."
So how do bacteria become drug resistant as in Fleming’s hypothetical illustration? Bacteria reproduce asexually. That is, a single microbe splits into two identical microbes, which turn into two more each, and so on. This happens quickly, and it happens imperfectly: factors both intrinsic and extrinsic to bacteria result in little mistakes taking place here and there when the organism makes new copies. For this reason, bacteria occasionally split into two different bacteria. If an environmental stressor such as an antibiotic is introduced, and one of the microbes happens to have a mutation that makes it resistant to the antibiotic, this microbe will successfully grow exponentially, leaving the drug-susceptible bugs in the dust.
Other times, however, bacteria have the ability to give each other genes they can use to survive an antibiotic attack. This is broadly known as horizontal gene transfer, or HGT. Horizontal gene transfer occurs both within and among species, making it potentially more powerful than a single species relying on mutations to live forever. HGT is driven by three mechanisms: transformation, transduction, and conjugation. Transformation refers to the introduction, uptake, and expression of foreign genetic material. Transduction instead is mediated by viruses, which transfer DNA from one bacterium to another. Third, conjugation is the transfer of DNA via a plasmid from a donor to a recipient cell upon cell-to-cell contact. A plasmid is a structure that can replicate independently of the bacterial chromosome, typically in the form of a small circular DNA strand. In fact, plasmids are so mobile that scientists use them all the time to manipulate organisms in research projects.
Given the immense prevalence of bacteria on Earth on the order of 1028 (1) and the even higher prevalence of viruses on the order of 1031 (2), it is safe to assume that horizontal gene transfer is an incredibly powerful mechanism without which any ecological system would be dramatically different, for better or for worse. What better way to underscore this point than with a story? New Delhi Metallo-ß-lactamase-1, or NDM-1, is a bacterial gene that confers broad-spectrum beta-lactam resistance, the type of antibiotic that penicillin is. Carbapenems are another type of beta-lactam drug, and these are supposed to be reserved for only hard-to-treat infections. As a result, the rise and spread of NDM-1 present a serious clinical challenge.
NDM-1 was first isolated in 2009 from a Swedish patient of Indian origin who was infected with antibiotic-resistant Klebsiella pneumoniae (3). Whether this was the first case of NDM-1 in the world or simply the first identified one is uncertain, but epidemiologists have concluded that NDM-1 did in fact first develop in India. In May of 2010, a case of E. coli expressing NDM-1 was identified in the United Kingdom in a patient who had visited India 18 months prior in order to undergo dialysis (3). In June 2010, three cases of Enterobacteriaceae isolates were identified in the United States in patients who, according to the Center for Disease Control, had all received recent medical care in India (3). In July of the same year, a cluster of cases arose in Chennai, India, with NDM-1-expressing Acinetobacter baumannii (3). In August 2010, The Lancet Infectious Diseases compiled a report on the gene, naming 37 cases in the UK, 44 in Chennai, 26 in Haryana, and 73 in other sites across Pakistan and India (4). Further study found that most of these strains carried NDM-1 on plasmids, implicating horizontal gene transfer through conjugation – rather than independent point mutations – as the source of the geographical explosion of NDM-1 (3). Within that same month, Canada reported its first case of an NDM-1 superbug in Brampton, Ontario, followed by a few other confirmed cases in British Columbia and Alberta (3). In September, Japan detected its first case of an NDM-1 strain in a patient who had previously been hospitalized on a trip to India (3). Epidemiological and environmental analyses have detected 20 different bacterial strains with NDM-1 just in drinking water across New Delhi, providing a clear pool for natural horizontal gene transfer (5).
These accounts show that both international travel and individuals’ use of multiple countries' healthcare systems served as a catalyst for the rapid spread of NDM-1. In today's highly interconnected world, horizontal gene transfer may occur more readily than ever before, facilitated by more frequent contact between organisms. Furthermore, natural reservoirs such as lakes or streams from which many people obtain drinking water are interactive environments for bacteria, too, to obtain survival genes. Rapid identification and isolation of patients harboring bacteria with NDM-1 have so far prevented serious outbreaks as the gene jumps across strains and geographic regions, but surveillance mechanisms need to be maintained for consistent prevention (3).
By 2014, most bacteria isolated worldwide with NDM-1 had originated from people colonized or infected in India who then traveled elsewhere (3). The emergence of NDM-1 in the Indian subcontinent is largely due to the fact that broad-spectrum antibiotics there do not require a prescription, given underlying economic incentives (3). As a result, strong selective pressure acted on bacteria to evolve and spread NDM-1 quickly and efficiently. Given the volume of modern international travel and the stubbornness of superbugs to antibiotic treatment, it is likely that NDM-1-bearing bacteria will continue to spread worldwide, making even more species hops.
The ability for physically diverse bacteria to successfully inhabit a new niche, such as a human body introduced with beta-lactam drugs or a body of water with runoff that contains excreted or disposed-of antibiotics, is largely driven by horizontal gene transfer, which is more rapid and geographically influential than useful mutations occurring from scratch in individual species. The emergence of multidrug resistance in every corner of the world within decades of the introduction of antibiotics is just more evidence of the potency and ubiquity of horizontal gene transfer when it confers adaptive traits.
The quantitative potential of horizontal gene transfer events is puzzling when compared to the size of bacterial genomes, which rarely exceed a few thousand genes. There are two possible explanations for this: either the actual rate of gene transfer is low, or the rate of maintenance of transferred sequences is low. Bacterial genomes are too small to contain arbitrary genetic elements that serve no purpose. As a result, despite the possibility that most transfer events go unnoticed due to their inability to become permanent, the beneficial events have become established across many species and have a huge effect on bacterial evolution. The most obvious effect, of course, is the transfer of antibiotic resistance. Ecological communities are defined by the positive and negative interactions between a variety of species, and mobile elements are highly favorable when it comes to facing a transient selective pressure like that imposed by antibiotics.
Horizontal gene transfer accounts for much more than the acquisition of antibiotic resistance. Plenty of microbes both in natural ecosystems and within organisms are constantly adapting to changing environments, and take advantage of genes from their own neighbors. As such, horizontal gene transfer provides the ultimate venue for bacterial diversification by the re-assortment of existing capabilities, but also for homogenization against negative pressures. Interspecific consistency in relative genome sizes, however, indicates that microbes are programmed to delete non-essential DNA: bacterial genomes can only maintain a finite amount of information, and the ability to sample foreign DNA provides a spectacular means to add, remove, and rearrange genes in a manner contingent upon their usefulness and essentialness.
So remember this the next time you go to the doctor, and make sure you do in fact have a bacterial infection before taking antibiotics. If you do take them, take the whole course even if you feel better before you’ve taken all the pills. Antibiotics were a miracle almost a hundred years ago and a given today, but we’re traveling backward in our ability to treat common infectious diseases. And this time, the solution won’t be something as simple as penicillin: all the easy drugs have been taken.
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