The rise of pathogenic bacterial resistance to antibiotic drugs is equal parts appalling and fascinating. Our relationship with bacterial diseases is cyclic: microbes infect our bodies and transmit themselves among us, we drive them back with medicine, a few unique bacteria survive and repopulate their own robust kind, and we must then find a new weapon against them. As in war or espionage, both opponents adapt to attack and exploit each other’s weaknesses. As bacteria evolve in response to the drugs we deploy, their strengths and weaknesses change; their strength manifests as resistance to the last drug treatment they endured--or else they wouldn’t be alive in the first place. Their weaknesses could be any of several things, but our job as worthy opponents is to exploit them.
The human body is besieged by all kinds of assailants: aside from genetic disorders like Huntington’s disease or illnesses acquired via non-living parts of the environment, like smoking-induced emphysema or a vitamin deficiency, we’re also vulnerable to infectious biological agents. Of these, viruses, such as poliovirus and chicken pox, are bare-bones replication machines made out of DNA or RNA and a few proteins; they need a host organism to infect in which to reproduce. Bacteria, such as E. coli, are self-sufficient life forms, although they’re simply single-celled and are distinct from other classes of life in structure and function. Fungi, such as yeast, and parasites, such as tapeworms, are more complex. Only certain kinds of viruses, bacteria, fungi, and parasites are harmful to humans, and we must use different weapons against each group of threat. We’ll focus here on antibiotics, the small molecules traditionally used to treat pathogenic bacterial infections.
The goal of battling any harmful infectious agent is twofold: to eliminate symptoms in the affected individual and to minimize infection transmission among people. In the case of pathogenic bacteria, we generally hope to do so at least by stalling cells’ metabolic processes, or at most by actually killing bacterial cells. These strategies must be both harmful to and specific to their targets; you could surely wipe out a Salmonella infection by setting fire to it, but your own body wouldn’t fare so well in the process.
Fortunately, antibiotics satisfy both requirements: they disrupt essential structures and processes found only in bacterial cells. Penicillin, the first widely used antibiotic in Western medicine, deactivates an enzyme that aids in building bacterial cell walls. Streptomycin, another commonly prescribed antibiotic, disrupts protein synthesis. Several other classes of antibiotic drugs have been discovered and distributed since the early 1940s, each with a different mechanism of action. For the first few decades after their introduction, antibiotics annihilated the incidence of infection with microbes like Streptococcus and even the deadly Mycobacterium tuberculosis. Some drugs were capable of thwarting several species of bacteria while others had more specific target ranges, but their combined antibacterial coverage thwarted dozens of diseases.
Inevitably and devastatingly, though, targeted bacteria evolve resistance to these drugs. Bacterial life cycles are usually under an hour, so selective pressure on beneficial traits such as antibiotic resistance acts much more quickly than it does in human hosts. It’s difficult to overstate the power of this advantage. During any given administration of antibiotics to an infected patient, a very small proportion of the resident bacteria may happen to bear a genetic mutation that confers resistance to the drug. If so, then those cells will survive the antibiotic course, persist and divide in the patient’s body, continue to sicken her, and will likely spread to other people, continuing to defy treatment. Multiply this scenario by the millions of bacterial infections reported annually, and it’s easy to imagine the evolution of antibiotic resistance in many diseases over several decades. Reality is even more alarming: some diseases have presented resistance within a year of antibiotic development.
Although several classes of antibiotics are available, many bacterial diseases have even developed multi-drug resistance. A few have been prominent in international news over the last few years: methicillin-resistant Staphlylococcus aureus (MRSA), is also resistant to erythromycin, arsenic, oxacillin, bacitracin, cadmium, and others. Transmission via skin-to-skin contact is rampant in dense community settings like prisons and hospitals, and MRSA can be lethal in people with challenged immune systems, as is common in those who are hospitalized. Clostridium difficile kills slightly over 10% of those infected, but it became four times more lethal over the seven years after 2000 as it acquired fluoroquinolone resistance. The list of redoubled threats grows: multi-drug resistant (MDR) Pseudomonas aeruginosa, extensively drug resistant (XDR) Mycobacterium tuberculosis, MDR Acinetobacter baumannii, b-lactam-resistant Enterobacteriaceae, penicillin-resistant Streptococcus pneumoniae (PRSP).
Many of their precise defenses are unknown, although some resistant bacteria have developed proteins that flush antibiotics from the cell. MDR Pseudomonas aeruginosa coats colonies of cells in a sheet of gel that restricts the penetration of some antibiotics. Some species have even retaliated with new offensive weapons called virulence factors; these are typically enzymes that chew up vital parts of host cells or small-molecule anti-host toxins.
Now, as a scientist, I find this interspecies sparring elegant and oddly inspiring, like a twisted version of a dandelion managing to grow through a crack in the sidewalk. As a vulnerable pile of human tissue, though, I’m terrified. And antibiotic resistance certainly presents a critical global health problem, exacerbated by failure to prepare for its inevitability. But there are still weapons in our arsenal that, if deployed immediately, may return pathogenic bacterial incidence to controllable levels – and they may do so more effectively than the antibiotics movement has so far.
A good defense
First, health care providers and the general public must take care to prevent bacterial transmission as much as possible. In hospitals, perennially important measures like proper hand washing and disposal of paper hospital gowns, latex gloves, and so on remain essential. Patients must be screened for as many antibiotic-resistant bacteria as is reasonable and isolated if they test positive. Perhaps the most novel measure, already in limited use, is to use antibacterial or water-repellent surfaces in hospitals wherever possible. Copper alloys are relatively inexpensive materials that happen to kill up to 99% of bacteria that would otherwise remain viable. Copper carries a positive charge, which can burst bacterial cells’ charge-sensitive membranes and then disrupt charge-sensitive metabolic processes inside. Similarly, pricier water-repellent materials far more effective than Teflon prevent the accumulation of the water that bacteria require to survive.
Withdraw the troops
Second, we must curtail the abuse of existing antibiotics to slow the rise of bacterial resistance. Doctors often prescribe them without first identifying a patient’s illness, in the hope that the antibiotics will work before symptoms become miserable, and under the lazy premise that they will not do much harm if the bacterial suspect is not the culprit. Hand sanitizers that contain the antibiotic triclosan also encourage bacterial resistance, although their alcohol base isn't a problem, because it kills bacteria on contact, and bacteria have not been known to develop resistance to alcohol, which targets bacteria broadly rather than one protein in particular.
In a more blatant mode of misuse, antibiotics are often administered to livestock because they happen to make animals grow larger; as a result, resistant bacteria are cultured in animals’ guts and are transmissible to humans through improperly cooked meat.
Ambush from all sides
Third, scientists must continue to subvert pathogenic bacteria at molecular and cellular levels. In theory, as long as new classes of antibiotic are discovered, we can maintain a buffer of them to use before their targets gain resistance. A new antibiotic called teixobactin, for example, is the only member of a new class that halts bacterial cell wall construction at an early step. The lab that developed teixobactin also introduced a method of high-throughput bacteria culturing in soil, which vastly increases the chances of discovering more antibiotics.
Other research has exposed more bacterial weaknesses. For example, it turns out that many of the genes for antibiotic resistance in bacteria exist on plasmids, small circular pieces of DNA. Plasmids can be present in many copies in a given cell, and one or more copies can be transferred between bacteria at almost any time--much more often than the stripped-down genome gets passed on during cell division. So, once that mutation that provides resistance has arisen, it may spread very quickly throughout bacterial neighbors. Fortunately, there is a method of using a small molecule to prevent this plasmid transfer from occurring, and as a bonus, it kills bacterial cells entirely.
However, the current state of antibiotic resistance still invites new approaches. Additionally, the growing knowledge about the helpful bacteria that colonize our bodies tells us that antibiotics can harm “good” microbes as well. One new plan of attack is to borrow a trick from the way that we prevent viral infections. Vaccines, which contain doses of inactivated virus, are administered before any exposure to the actual virus to be avoided takes place. As a result, the body develops immunity to the virus in question. Vaccines can be developed against bacteria as well, and a few proof-of-concept designs are implemented in the literature. One is a cheap, inert gold nanoparticle that has been coated in inactive parts of bacterial cell surface, so that the human immune system can recognize and build immunity to it. Vaccines have been immensely successful in reducing and sometimes even eradicating certain viruses, and they could have similar success against pathogenic bacteria.
Lastly, potentially the most promising route is to use bacteria’s own natural enemies against them with a method called phage therapy. There are viruses called bacteriophages, or simply phages, that only infect certain bacteria. Upon infecting their bacterial hosts, one or more phages replicate and then burst the bacterium in order to move on and infect more cells. Phages are observed so commonly that we can reasonably guess that most or all pathogenic bacteria have a naturally occurring phage counterpart. They are fairly easy to isolate from bacterial cultures, making their discovery more likely than that of new antibiotics. And unlike a small antibiotic with a single mechanism of action, phages have evolved to recognize, penetrate, replicate within, and burst specific bacterial species; any given bacterium is less likely to be able to thwart a phage than an antibiotic in a single round of mutation. We must watch out for a few phages that have acquired genes that code for harmful virulence factors from their bacterial hosts, but these are simple to screen out. The drawbacks of teaming up with phages are that we would have to amass a collection of hundreds of them, one for each target bacterial species and subspecies, and that intellectual property rights surrounding phage patents are nebulous in the U.S. Frustratingly, antibacterial phage therapy is a risky gamble for drug developers.
It’s difficult to say which approaches will be most effective against harmful bacteria, and for how long. Evolution is unpredictable, and some strain might develop water retention as a defense against water-repellent surfaces, or another might annually develop resistance to a vaccine, the way that the influenza virus does. But the greater the variety of weapons we keep in our arsenal, the more we can outwit pathogenic bacteria before they become superbugs.
This article has been edited for clarity.
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