Unexpected outbreaks of viruses like Zika and Ebola may seize headlines, but there is a less exotic and even more formidable threat on the horizon. “A post-antibiotic era,” says the World Health Organization, “in which common infections and minor injuries can kill—far from being an apocalyptic fantasy—is instead a very real possibility for the 21st century.”

Microbial pathogens, including the kinds of bacteria and fungi we come in contact with every day, are designed by evolution to play cat and mouse with a host’s immune system. Driven by the excessive and often unnecessary use of antibiotics—whether in animal feedstocks or to treat human infection—these nimble organisms are mutating at an accelerating pace, some capable of foiling even last-resort medications. “It’s very scary,” says Elizabeth Nolan PhD ’06, an associate professor in the Department of Chemistry, whose research on infectious disease is aimed at the problem of antibiotic resistance. “There are more and more drug-resistant strains of bacteria being found, strains that can travel around the world wherever humans go.”

In the US alone, antibiotic-resistant superbugs currently cause 2 million cases of illness and 23,000 deaths a year, according to the Centers for Disease Control. A recent British government assessment projects an astonishing 10 million annual deaths globally from superbugs by the year 2050.

Given these stakes, says Nolan, “We really need people to think outside the box.” And that is precisely what she and a contingent of fellow MIT scientists have set out to do. Deploying the latest technologies and working within and across diverse fields in science and engineering, these researchers are developing new tactics in the battle against superbugs.

Starve them out

Nolan’s chosen strategy uses metals essential to an organism’s survival. “Humans have three to five grams of iron inside our bodies, which is critically important for our health,” she says. “Many kinds of bacteria also need this iron, but it’s hard for them to find it.” During infection, microbes and hosts compete for iron and other metals, and this contest has provided Nolan with ideas for new therapies. In a series of studies, she has investigated the metal-acquisition systems in such pathogenic bacteria as Escherichia coli and Salmonella. Inside the infected host, these bacteria fabricate molecules called siderophores, which are set loose in the environment outside of cells.

“Siderophores scavenge iron from the host, and deliver it to the bacterial cell,” says Nolan. The human immune system fights back through a metal-withholding response, which includes unleashing proteins that can capture certain iron-bearing siderophores. In short, as Nolan puts it, “There’s a total battle for nutrient metals going on. The question is whether the host outcompetes the microbe, or vice versa.” To give an edge to the host, Nolan has been exploring several strategies. One involves tethering antibacterial cargo to siderophores and unleashing them against specific pathogens. Another, in partnership with researchers at the University of California, Irvine, is designed to boost the immune system’s metal-withholding response by generating siderophore-capturing antibodies in the host. In early laboratory tests of this method, Nolan and her partners successfully inhibited the growth of Salmonella. “We are really excited about the possibility of immunizing against bacterial infections,” she says.

Nolan sees great potential in fundamental research aimed at revealing the structural and functional properties of the human immune system’s metal responses. In one recent study, for instance, she discovered that calprotectin, an abundant, metal-sequestering human protein that is present at sites of infection, has uniquely versatile properties that allow it to seize whatever metal an infectious microbe requires for its survival. This is the kind of discovery that might someday generate a new antibiotic therapy. It is another reason why Nolan is confident, she says, that “deciphering the pathways used by organisms and hosts for sequestering nutrient metals will lead to new insights for preventing and treating disease.”

Chart their defenses

With the help of the latest technologies, it is now possible to map microbial behavior in the finest detail.

“We couldn’t easily explore drug resistance before, but CRISPR technology makes it much easier for us to manipulate the genome,” says Gerald Fink, another researcher working in this area, who is the Margaret and Herman Sokol Professor in Biomedical Research at the Whitehead Institute, and American Cancer Society Professor of Genetics at MIT. Fink is using the popular DNA-editing technology CRISPR-Cas9 to unravel antifungal resistance in the human pathogen Candida albicans.

Why study fungi? Unlike bacteria, whose toxins damage host cells, they often do harm simply by growing in the wrong places—so while C. albicans “ normally lives in our gut happily and harmlessly,” says Fink, it can prove deadly if it moves elsewhere (by way of catheter or prosthesis, for example). Fungi, like bacteria, can also develop resistance to antibiotics. Masters of disguise, they evolve mechanisms to evade detection by altering the composition of their cell membranes. Fink notes that there is huge natural variation in resistance among fungi. “Bacteria and fungi have been here for hundreds of millions of years, and there’s no game they haven’t played,” he adds. “We’re just trying to keep one step ahead.”

Fink previously created a working model of harmless baker’s yeast to serve, in his words, as “a paradigm for all higher cells.” Now he is working to create a comparable paradigm with C. albicans, a fungal pathogen whose invasive behavior can range from superficial skin infections to life-threatening systemic infections. Using CRISPR, Fink’s lab is systematically snipping out genes to determine which ones help C. albicans live outside of the gut and also survive immune system defenses. Fink’s lab has already found a number of genes promoting C. albicans’s drug resistance, and hopes that as the entire genome is decoded, “we can know what the enemy looks like and think about designing new antibiotics.” CRISPR-based tools have also begun to revolutionize the detection of infection. A new method that uses a modified genome editing enzyme, Cas13a, comes from James Collins, MIT’s Termeer Professor of Medical Engineering and Science and a member of the Broad Institute at MIT and Harvard.

Collins has collaborated with Broad colleague Feng Zhang, James and Patricia Poitras Professor in Neuroscience, and others to develop a highly sensitive diagnostic platform they named SHERLOCK (for “specific high sensitivity enzymatic reporter unlocking”). Using  chemicals and biomolecules freeze-dried on a piece of paper, SHERLOCK not only identifies a bacterial pathogen quickly from just a few strands of DNA, but also determines whether that microbe is resistant to certain antibiotics and susceptible to others. At a cost of 61 cents per test, SHERLOCK—which can also detect cancer mutations and viruses such as Zika—is cheap and durable enough for any clinical setting, including those in developing countries. “It’s a platform with transformative power,” Collins says.

Send in your best agents

In addition to his work in diagnostics, Collins is taking direct aim at bacterial defenses, fabricating what he calls “next-generation antimicrobial agents” that could overcome antibiotic resistance.

A founder of the new field of synthetic biology, Collins has spent much of the past decade developing intricate biomolecular models of bacterial cells that shed light on their metabolic state—how they produce and consume energy, and what conditions promote or stymie growth. He has taken a special interest in “persisters,” strains of bacteria that deviously go dormant in the presence of antibiotics, leading to the kind of chronic infections plaguing tuberculosis and cystic fibrosis patients.

Recently, Collins and colleague Graham Walker, American Cancer Society Professor of Biology at MIT, have worked out how bacterial metabolism determines whether an antibiotic “will kill the bug, stop it from growing, or make it more resistant,” says Collins. What’s more, their labs have engineered a way to manipulate bacterial metabolites, substances produced by bacteria to regulate their own development, to make these pathogens vulnerable to antibiotics.

Metabolic tuning could resensitize previously antibiotic-resistant strains. “This has largely been overlooked by the drug discovery community and the clinical community, but we think it’s a gold mine that can be harnessed to boost our existing arsenal of antibiotics,” Collins says. Up to 50% of all the antibiotics prescribed in the US are not needed or are not optimally effective as prescribed.

Collins’s group is also designing new weapons to attack pathogens. “We’re looking to engineer and enhance bacteriophages, naturally occurring viruses that go after bacteria, to make them more effective.” In one venture, they have endowed bacteriophages with enzymes that break up biofilms, the gooey matrix produced by bacterial pathogens that often kicks off infections in artificial joints, implants, and pacemakers.

These new tools will be arriving not a moment too soon, he says. “Nature is remarkably clever, and the next pandemic is coming, and it could be a bacterial pathogen,” he says. “I hope we will be in a good position to address it.”

Try diplomacy

While she shares this hope, Katharina Ribbeck, associate professor of biological engineering, takes a radically different view of the problem: “We need to step out of the arms race and instead form an alliance with problematic microbes,” says Ribbeck. “But how?”

In a word: mucus. Ribbeck sees myriad opportunities for coping with problematic pathogens by exploiting this primitive product of the immune system. Trillions of microbes, many benign and performing vital functions, live inside mucus, which lines the intestinal tract, lungs, mouth, nose, and other orifices in humans, coating some 2,000 square feet of internal surface area.

“Somehow our mucus keeps microbes in check, whether they are beneficial or serious pathogens,” says Ribbeck. “Mucus doesn’t kill them, like antibiotics, but it tames them.” In recent studies of two types of Streptococcus bacteria found in saliva, one associated with cavities and the other with healthy oral conditions, Ribbeck gained insight into how the infrastructure of mucus keeps the two types in balance. “Preventing certain microbes from teaming up and surrounding themselves with a protective biofilm is at the core of mucus function,” she explains. “In this state, they can’t dominate as easily, and are more vulnerable to the immune system.”

Now Ribbeck seeks to leverage “biochemical motifs” of mucus to achieve a new repertoire of responses to microbial pathogens. She’s discovered mucus components that can be used to suppress and dissolve the dangerous biofilms built by pathogenic bacteria, and with natural and engineered polymers, believes she has found a way of dislodging tenacious pathogens, thereby preventing infections and empowering the immune system and antibiotics to perform better.

“We could apply our synthetic dressing on real wounds and on mucosal surface infections such as those in the digestive tract, mouth, or lungs, allowing both antibiotics and the immune system better access to subdue harmful microbes,” she says. “This could solve some of the most vexing problems related to resistance.”

Ribbeck’s strategy depends on strengthening the body’s beneficial microbes, striking a balance with pathogenic strains and encouraging a diverse microbiome. “Microbes don’t necessarily want to harm us; they just want a safe place to eat and divide,” she says. “By harnessing mucus to help us with microbes, we can domesticate them and find better ways to protect ourselves.”


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