Targeting an Old Foe

M. tuberculosis is a tenacious germ. Armored in a thick, waxy wall impervious to water, the bacterium can lie dormant in the lungs for decades, waiting for a weakness in its human host.

As drug-resistant strains of TB spread around the world, Luiz Bermudez works urgently on new treatments. (Photo: Karl Maasdam)

By Lee Anna Sherman 

M. tuberculosis is a tenacious germ.

Armored in a thick, waxy wall impervious to water, the bacterium can lie dormant in the lungs for decades, waiting for a weakness in its human host. When airborne on a cough or a laugh, it can infect a new victim in a simple breath of air. With a flip of a gene, it can dodge healing drugs by mobilizing legions of mutant clones.

Once considered a disease of the past (the last of Oregon’s sanitariums were closed in the 1970s), TB is making a comeback. Around the world, more than 8 million people are infected yearly, and 2 million die. Piggybacking on the epidemic of HIV/AIDS, the opportunistic TB pathogen is more dangerous than ever. Some 12,000 strains, each bearing a distinct “genetic fingerprint,” have turned up in hospitals, prisons, refugee camps and clinics.

In OSU’s biohazard lab, thousands of these strains are undergoing experiments that could give the world its first new TB therapy in four decades. Luiz Bermudez, M.D., is leading an investigation into the anti-TB properties of a drug commonly used to treat malaria. The two-year project is funded by a nearly $1 million grant from the Bill and Melinda Gates Foundation, a major partner in a worldwide race to defeat M. tuberculosis.

Some strains have developed fierce resistance to the powerful drugs rifampin and isoniazid, the “backbone of modern anti-TB chemotherapy,” explains Bermudez, a professor in the College of Veterinary Medicine. Until recently, scientists believed this potent cocktail had virtually wiped out the killer disease. But new drug-resistant strains have emerged. “Now it is very common for a healthy person to acquire drug-resistant bacteria directly,” Bermudez warns. “In terms of public health, that is a nightmare.”

The Centers for Disease Control (CDC) has designated some strains as “extensively drug resistant” (XDR) – that is, they survive just about anything doctors throw at them. In the U.S., 17 cases of XDR-TB have been reported.

With drug-resistant TB raging in hotspots such as Russia and Argentina, the Gates Foundation and others (including billionaire philanthropist George Soros, the World Health Organization and the World Bank) have mounted an aggressive 21st-century battle against the resurgent germ.

Of Germs and Genomes

Bermudez studies a family of infectious pathogens called mycobacteria, of which M. tuberculosis is one. Hansen’s disease, or leprosy, is another. A third is M. avium, which attacks humans whose defenses are compromised by conditions such as HIV-AIDS.

Bermudez and his colleagues – pharmacy professor Mark Zabriskie and several post-doctoral assistants – work with the rod-shaped microorganisms inside OSU’s Biosafety Level-3 laboratory. (Level 3 is designated by the CDC for airborne pathogens, including anthrax, West Nile virus, typhus and yellow fever.) The Gates-funded study focuses on Mefloquine, a drug that has proven extremely lethal to M. avium, both in test tubes and in animals. But there’s a downside: Mefloquine causes neurological side-effects – from depression to paranoia – in 15 percent of patients.

In a recent breakthrough, Bermudez was able to isolate the most active compound in Mefloquine. It turned out to have a dual benefit. “The compound that is most effective against mycobacteria is the least toxic of the compounds,” Bermudez says.

The agent has also proven effective against M. tuberculosis in test tubes. The researcher’s goal now is to pinpoint the “essential target” on the DNA of resistant TB mutants. That is, he’s looking for the key metabolic gene the germ needs to survive. Once he finds it, scientists can develop new drugs that attack TB in new ways. “Most antibiotics shut down bacteria by inhibiting protein synthesis,” Bermudez says. “For Mefloquine, we don’t yet know what the mechanism is. But it appears to do more than just inhibit the mycobacteria – it kills it.”

In a world where everyone is only a plane ride from everyone else and M. tuberculosis can be transmitted in a cough, a sneeze, even a hymn sung with gusto in church, the stakes couldn’t be higher.
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