Beyond Antibiotics

Late on the night of December 26, just three days after I had given birth to my son and two days after receiving two blood transfusions for complications, I was back in the hospital. This time, I had gone straight to the emergency room. There we were: me, my days-old baby, and my husband. The ER doctors put us in a separate room to try to isolate us from the contagion filling the hospital floor. But a few hours in, my husband started vomiting. He was asked to leave if he did not wish to become a patient. My baby could not stay with me. It was dangerous just having him there. I was alone.

I had left the hospital with my baby on Christmas Day. As best I can recall, the discharge nurses had instructed me to call back if I developed a fever over 101˚ F. The day I checked into the ER, our thermometer had read just a few tenths of a degree over.

The doctors knew I had recently been in the hospital, and they knew that I had lost a lot of blood. But they had no idea which bacterial strain was causing the fever, so they hedged their bets, giving me two different antibiotics—one for MRSA (methicillin-resistant Staphylococcus aureus), a common antibiotic-resistant strain of staph bacteria, and another antibiotic for the common infection culprit E. coli. When my hospital roommate heard I was on a drug for MRSA, she requested to be moved. I lay in bed alone, ordered hospital food, and pumped tainted breast milk.

In the days that followed, I started eating ice in the hopes that it would trick the nurses’ thermometer and they would let me go home. I fooled no one. This low-grade fever would keep me in the hospital for twice as long as my massive blood loss did following birth.

My two hospital stays illustrate how the script for medical care has flipped over the last several decades. In many ways, a hospital acquired infection has become more serious than an uncontrolled bleed. Bacteria and other pathogens are developing multi-drug resistance, and our last, best strategies are failing.

You may have heard the rumblings. Doctors have been warned not to over-prescribe antibiotics. Consumers have been admonished against the antibacterial soaps and creams. We can now buy meat and dairy marked “animals not treated with antibiotics or hormones” in the supermarket. But those measures are only stop-gaps. They will only, perhaps, slow the pace of resistance.

For years, researchers and doctors have known this. Responsible antibiotic use isn’t enough to win the pathogen war—it “reflects an alarming lack of respect for the incredible power of microbes,” wrote a group of infectious disease experts from across the U.S. in a 2008 “Call to Action” paper. After all, they write, microbes have been evolving and adapting for 3.5 billion years. Thanks to their combination of genetic plasticity and rapid generation time—they can undergo as many as 500,000 generations during one of ours—they are especially good at overcoming evolutionary obstacles.

Antibiotic resistance is just another byproduct of those abilities. It has evolved because patients don’t complete a full course of drugs or because animals receive drugs they don’t really need or because a college kid slathers his apartment in antibacterial spray. Antibiotics kill most but not all of the bacteria they encounter. The strongest ones live. These reproduce and pass on their advantages, and sometimes they get together and swap genes. Eventually, the resistant types grow very, very resistant.

It wouldn’t be a problem if bacteria weren’t evolving resistance faster than we have been able to respond. New antibiotics are difficult to produce, and they don’t make as much profit as drugs for chronic disease, so there has been a dearth of investment. “Why it feels like it’s happening right now is that there aren’t really new antibiotics coming down the pipeline,” says Dr. Carmen Cordova, a microbiologist who works for the nonprofit National Resources Defense Council. “We don’t have really a plan B.”

Three years ago, science journalist Maryn McKenna published an award-winning article in which she imagines a modern environment devoid of antibiotics. It’s a return to the medical dark ages in which illnesses like tuberculosis, pneumonia, and meningitis are death sentences. It would mean that burn victims, surgery patients, laboring mothers, and those undergoing chemotherapy would have to worry constantly about succumbing to infection.

President Barack Obama has called antibiotic resistance “one of the most pressing public health issues facing the world today.” A conservative estimate from a British project called the Review on Antimicrobial Resistance states that, if left unchecked, antibiotic resistance will cause 10 million human deaths per year—more than the number of people who currently die from cancer and diabetes combined.

The threat is looming. Late last year researchers identified bacteria resistant to a last-resort antibiotic in Chinese raw chicken and pork meat, slaughterhouse pigs, and hospital patients. The resistant gene has since been identified in bacteria across Asia and Europe.

But we are fighting back. President Obama has asked Congress for $1.2 billion over five years for developing new diagnostic tools, creating a database of antibiotic resistant diseases, and funding research to better understand drug resistance. It joins other, ongoing efforts to identify promising new candidates. In labs and universities around the world, researchers are hard at work identifying, testing, and perfecting strategies that go well beyond what, today, we call antibiotics.

Knocking Out Communications

We used to think that bacteria were dumb. We thought they ate, pooped, divided, and not much else. We now know that this story is much too simple. Bacteria communicate, keep tabs on their environment, and respond and react. They ask how many others are around and how they are doing, and only when a certain number have congregated do most pathogenic bacteria turn virulent. The danger is in numbers.

Of course, sometimes they gain the upper hand despite our best efforts. But what if there was a way to hide them from one another? What if we could shut down their party before it starts? That’s the idea behind quorum sensing inhibitors.

P_vortex
Paenibacillus vortex uses cell-to-cell communication to form colonies with complex shapes.

Quorum sensing inhibitors (QSIs) are molecules designed to interfere with pathogen communication. When bacteria go looking for friends, they put out small molecules like little flags, saying, “I am here!”  For the past two decades, researchers have been working to develop strategies that interfere with every step of the process, by halting production of these flags, obscuring them so that other bacteria cannot recognize them, or blocking responses when they are recognized.

The results, so far, have been promising. According to Vipin Kalia, a researcher at the Institute of Genomics and Integrative Biology in Delhi India, such quorum sensing inhibitors are less likely to lead to bacterial resistance because, “Antibiotics create a pressure on bacteria because their survival is under threat. QSIs are not threatening their existence and survival.” Several of these inhibitors have been shown to reduce virulence in animals, Kalia says, and two have made it to clinical trials.

Still, none are currently used to treat human diseases, and while it may be more difficult for bacteria to develop resistance to these inhibitors, it is not impossible. In fact, it may already be happening. In a 2014 paper in the journal Microbial Ecology, Kalia and his colleagues write that “evidence is accumulating that bacteria may develop resistance to QSIs.” It appears that communication is important enough to bacteria that they have several different channels. If one path is blocked, they try to use another. “Apparently” the researchers write, “bacteria do not even need to undergo any genetic change to withstand quorum sensing inhibitors.”

QSIs may buy us some time, but will it be enough? Fortunately, there are other options.

Creating an Inhospitable Environment

The development of new antibiotics has often relied on tweaking existing drugs. It’s a simpler approach than developing an entirely new class of antibiotics, but the modifications are often small enough that bacteria can adapt relatively easily. Fortunately, plants, animals, fungi, and other microbes have been battling it out long before we arrived, and they have evolved a few good tricks.

One, antimicrobial peptides (AMPs), were first identified in silk moths and are now known to be an innate immune response in almost all organisms from algae and plants to the entire animal kingdom. AMPs use differences between the membranes of a host cell and a bacteria to selectively target only the harmful microbe invader. Bacteria tend to be negatively charged, while mammalian cells tend to be neutral. The positively charged peptides glom onto the bacteria’s membrane and punch holes in it. Rather than having to recognize specific targets on the cell membrane, as traditional antibiotics do, AMPs grab any bacterial membrane that doesn’t belong and shoot it full of holes.

AMPs happen to be much more resistant to bacterial adaptations. Despite their ancient origins, AMPs remain effective weapons today. “Bacteria can become resistant to antibiotics by simple modifications of the receptor where the drug attacks. To become resistant to AMPs…they need to change their entire membrane chemistry,” says Karen Lienkamp, a junior research group leader working on AMPs at the University of Freiburg in Germany.

Right now, researchers are working on making materials that have synthetic versions of AMPs, or SAMPs, on the surface. These specially engineered surfaces help reduce microbe contamination on hospital equipment, in the air, and on clothing. Specifically, they prevent biofilms—clumps of bacteria that form protective nets around themselves. “Biofilms are the ‘root of all evil,’ ” Lienkamp says. “Studies with regular antibiotics have shown that you need up to 1,000 times the concentration to kill bacteria that are encapsulated in a biofilm.”

Other strategies to prevent bacteria from taking up residence on hospital surfaces include extra-slippery materials and materials that shed layers to prevent buildup. Yet as promising as they are, anti-fouling surfaces are only useful for prevention. They won’t help someone who already has rampant infection. What we really need are ways to identify what ails us, and quickly, with customizable drugs to treat them.

Faster Identification

Justin O’Grady is a lecturer in medical microbiology at the University of East Anglia in the United Kingdom. Last year, he and others published a paper in the journal Nature Biotechnology about a technology that can take a sample of blood and, in six to eight hours, identify the bacteria that is causing an infection. In hospitals and labs today, it typically takes two to five days.

The device is a gene sequencer called the MinION, which reads the bacteria’s genetic signature within minutes. It’s small enough to plug into a computer’s USB drive, and at around $1,000 for the necessary equipment, it doesn’t cost nearly as much as traditional laboratory-grade gene sequencers. Moreover, the device, when given another day or so to process the sample, can also identify which genes in an invading bacteria are responsible for the antibiotic resistance. “This would be a personalized medicine approach to antibiotic treatment,” O’Grady says.

Minion
A MinION sequencer

While other molecular identification technologies exist, sequencing technologies like the MinION are broad-spectrum microbe detectors. “The advantage of sequencing for this approach is that you get an unbiased diagnosis,” O’Grady says. “You don’t need to know anything about what pathogen might be in there.”

If something like MinION had been available when I was in the hospital, my experience would probably have been quite different. It wouldn’t have taken doctors five days to determine the root cause, getting me home sooner and saving both the hospital and the insurance company a significant amount of money. I also would not have been administered ineffective antibiotics, preventing a small amount of evolved resistance.

Instead of doctors treating their patients with best-guess antibiotics while they wait days for culture results to come back, sequencing technologies like these will tell them what is going on by the time the nurse comes around with the second dose. “If we can change the way that we prescribe antibiotics, we can improve antibiotic stewardship and we can improve patient management at the same time.” O’Grady says. “The patient receives better treatment quicker, and society benefits because we keep our potent antibiotics for those who need them most.”

Building a Library

The most promising new antibiotics may, counterintuitively, come from the bacterial domain itself. Though nature’s bacterial library could hold a multitude of undiscovered antibiotic recipes, sifting through its diversity is a daunting task: Most bacteria found in the environment—99%—will not grow on a petri dish in traditional cell culture.

We may soon be able to unlock that library, though, thanks to the work of Kim Lewis, director of the Antimicrobial Discovery Center at Northeastern University in Boston. Lewis reported last year in the journal Nature that he and his colleagues found a way to culture bacteria from the soil, which have been notoriously difficult to grow in the lab because they rely on signals and molecules from neighboring bacteria to grow.

Lewis and his colleagues decided that rather than try to painstakingly recreate those conditions, they would just bring a little soil back to the lab. They started by collecting a small scoop of soil, rinsing it in water, mixing the water into culture medium, and then squirting the mixture into a device they developed called the iChip. They then placed the iChip into a bucket of the same soil kept in the lab. After a month they pulled the iChip out, cultured the bacteria, and observed what was growing. The bacteria were still growing in agar—not their ideal environment—but they were happier after the month spent back in the soil.

“Ten percent of uncultured bacteria from the natural environment require growth factors from neighboring bacteria,” Lewis says. Their soil vacation seems to make the bacteria stronger, more adaptable, and more likely to grow on the iChip.

Eager to build their library, Lewis and his colleagues began collecting from their back yards. If someone went on vacation, they were given a kit to bring back a sample. One collaborator took a serendipitous trip to Maine and returned with a completely new genus of bacteria, one that produced an incredibly effective antibiotic that kills other types of bacteria, which they named teixobactin. In experiments with human cells and in mice, teixobactin proved exceptionally effective at killing Clostridium difficile (a resistant bacteria that causes ulcers and is most effectively treated with fecal transplants) and Staphylococcus aureus, the bacteria whose resistant strains are called MRSA.

Teixobactin must complete many hurdles before it can become a drug offered in the doctor’s office. It will need to be formulated to remain active inside the human body, toxicology tests will need to ensure that it does not confer nasty side effects, and experiments will need to determine other medicines it may interact with.

Lewis is working with a company to improve the teixobactin’s solubility, and he estimates that it will take two years to get to clinical trials, which will then take at least another three years. So, even in the best case scenario, texiobactin will not be helping us to fight off antibiotic resistant disease for the next five years.

In the Meantime

Of course these are not the only promising technologies being developed to prevent, fight, and treat antibiotic resistant diseases. Bacteria-targeting viruses, gene editing, nanoparticles, and shotgun-like strategies using multiple drugs are all brimming with potential.

But each of these needs time—time for research and development and optimization. In the meantime we will have to trust that our current technologies and common sense prevention provides the window we need. (Please, everyone, wash your hands.)

As for my brush with an antibiotic-resistant infection, I eventually returned home to my husband and children. On the fifth day, lab results revealed why the drugs were not working. I did not have MRSA. I did have E. coli, but the strain I had was resistant to the drug they were giving me. Neither of the antibiotics was having any effect.

The doctors had made their best guesses, but those guesses had been wrong. The hospital let me leave with new antibiotic and a tube inserted into a vein close to my heart. Don’t let that tube get dirty, they warned me, or the infection could kill you. Don’t get air in the line, they warned me, or that could kill you too.

To say I was careful is an understatement. Three times a day I fed my newborn, put him down to sleep, and followed the hour-long procedure. Years of work in a nanotech laboratory had taught me how be meticulous. After two weeks, a nurse came and removed the line next to my heart. The treatment had worked. The bacteria I acquired at the hospital had not evolved resistance to every weapon in our arsenal. At least, not yet.