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New Strategies to Fight an Ancient Disease

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New Strategies to Fight an Ancient Disease Scanning electron micrograph of Mycobacterium tuberculosis bacteria, which cause TB. Credit: NIAID

New Strategies to Fight an Ancient Disease

By Christy Brownlee 

August 2017 --Gyanu Lamichhane, has many happy memories of growing up with his grandfather in Nepal. When his parents were at work, they explored their town together, and bought a special treat, popsicles. “He was my best childhood friend,” Lamichhane remembers.

But those happy memories are tainted by what happened when Lamichhane was in the eleventh grade. He knew his grandfather had tuberculosis (TB), but Lamichhane and his family didn’t know how serious it was. His grandfather didn’t respond to the usual drug treatments because his particular strain of TB was resistant to all drugs that were available at the time. Lamichhane remembers holding buckets next to his grandfather while he coughed up blood. When he died, Lamichhane was devastated — this eventually motivated him to find new ways to fight the disease. 

“All I want to do is kill [TB]. It’s a personal thing for me,” Lamichhane says. “I couldn’t save my grandfather, but if I could save someone else, that would be my way of saying I’m sorry.”

Now an associate professor in the Johns Hopkins School of Medicine’s Division of Infectious Diseases, Lamichhane works in the to discover weaknesses in Mycobacterium tuberculosis (Mtb) — the bacterium that causes TB — and new ways to exploit them. One of his closest colleagues is , who co-directs the center and was Lamichhane’s Ph.D. mentor while he attended graduate school at Johns Hopkins. 

Bishai has been part of the center since it launched in 1997. “When we said we wanted to be a center, the university told us to just print our own letterhead,” he remembers. Now, the center has become one of the world’s leaders in TB research, equipped with a 3,000 square foot biosafety level-3 animal facility and two biosafety level-3 labs. 

A large part of Bishai’s contribution to this program, he explains, is simply trying to understand Mtb’s mechanism for making humans sick. For all the billions of research dollars that have been spent globally on TB, Bishai says, embarrassingly little is still known about the basics behind infection, limiting the development of new and more effective or efficient treatments.

A long-running theme of Bishai’s research is the regulation of Mtb’s 4,000 genes. His and other researchers’ work established that when this bacterium enters macrophages — the immune cells it infects in human lungs — the expression of some of these genes increases while that of others decreases. One set of genes that has an uptick in activity is those responsible for making a set of signaling molecules called cyclic nucleotides. 

These molecules are important for a wide variety of functions in human biology, explains Bishai, and several drugs directly target them. For example, some popular asthma drugs help build up the levels of one of these cyclic nucleotides, cAMP, to relax the bronchial tree. Sildenafil, better known as Viagra, also helps increase levels of cyclic nucleotides to treat pulmonary arterial hypertension and erectile dysfunction.

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Papers published by Bishai and his colleagues in 2009, 2015, and 2016 have shown that when Mtb secretes selected cyclic nucleotides into macrophages, they interfere with the human cells’ innate signaling, causing pointed hotspots of macrophages called granulomas—a signature feature of TB—that promote inflammation and death of healthy tissue. Although this disrupted signaling appears to one of Mtb’s most powerful weapons, Bishai notes, it could also be one of its weak links. Building on this research, he and his colleagues tested combining standard antibiotics used to treat TB in a preclinical model with two drugs used to build up native human cyclic nucleotides: sildenafil and cilostazol, a drug used to treat symptoms of peripheral vascular disease. This approach accelerated a cure in mice, shaving one to two months off the typical six-month treatment time.

While these studies have been aimed at developing therapies to boost the host’s defenses to TB, Lamichhane’s work has primarily focused on attacking Mtb directly. One of this bacterium’s Achilles’ heels, Lamichhane says, is its cell wall—the structure that gives Mtb its shape and provides protection for its contents. 

Lamichhane explains that if Mtb were a house, the cell’s outer membrane would be like siding, the inner membrane would be like drywall, and the cell wall would be the bricks and mortar. “You can take the siding and drywall off,” he says, “and the house would be fine. But if you take out the bricks and mortar, the house will fall apart.”

Like bricks that can be placed with the short side facing out or tucked in, the peptides in peptidoglycan—the major component that makes up the cell wall—can also be oriented in one of two ways. While the beta-lactam family of drugs, which include penicillin, inactivate the enzymes used to build one orientation, Mtb uses a different set of enzymes to build its cell wall with the opposing orientation, rendering these drugs ineffective.

Recently, Lamichhane and his colleagues discovered Mtb’s set of cell wall-building enzymes. They also discovered that a family of existing antibiotics, known as carbapenems, can dismantle this enzymatic pathway, inhibiting cell wall growth. 

This discovery is useful for fighting not only TB, Lamichhane notes, but also other mycobacteria that take advantage of this set of enzymes. These include Mycobacterium abcessus and Mycobacterium avium, which tend to infect cystic fibrosis patients. Working with infectious disease colleagues at The Johns Hopkins Hospital, Lamichhane has already helped implement these drugs to fight infections in cystic fibrosis patients who had few other options. He and other colleagues are using these findings to start the arduous process of developing new antibiotics that specifically target these pathways for TB.

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Despite the promise of their work, Bishai and Lamichhane say, it’s been difficult to attract the interest of pharmaceutical companies that can move these concepts through the necessary hurdles to become marketable treatments. Although TB is currently the world’s top infectious killer, it’s relatively rare in the U.S., diminishing the perceived need for new treatments. Publicly traded pharmaceutical companies might see long-term medicines such as blood-pressure drugs that patients take for decades as better investments than a short-term antibiotic, says Lamichhane.

    But Bishai says he dreams of a future when the inherent value of their work leads to treatments that are more effective and significantly faster than those available today. “Before I’m a grandfather,” he says, “I’d like to see a 30-day or 60-day blister pack for TB, where a patient takes a pill every day to be cured.”