New anti-TB drug couples double-punch, low toxicity
Needed: Deep pockets to put it through trials
A compound that has links to the strange but sturdy bacteria known to flourish in deep-sea vents displays some anti-TB properties that make it a tantalizing newcomer on the pharmaceutical scene, researchers say.
The new compound, PA-824, appears to inhibit both active and latent TB mycobacteria, says Ken Stover, PhD, senior director of research biology at PathoGenesis Corp., the Seattle-based drug company that developed the agent.
PA-824, one of a series known as the nitroimidazopyrans, or NAPS, seems to behave in a truly novel way against TB, Stover says.
"The NAPS appear to act on both protein and lipid biosynthesis," he says. Little is yet known about how PA-824 acts against lipid synthesis in the waxy-coated TB mycobacterium, and researchers know even less about how the agent has affected the bug’s ability to make proteins.
What’s clear is that so far, no strain of TB in the wild has been found capable of standing up to PA-824, not even some strains of multidrug-resistant TB, Stover adds. In mice, the agent performs as effectively as isoniazid, the standard of comparison.
The NAPS are analogues of nitroimidazofurans, a related compound that originally was developed as a radiosensitizing agent, he says. Researchers already had noted that nitroimidazofurans had interesting anti-TB activity; the trouble was they also had mutagenic properties. By changing a five-member ring into a six-member one, PathoGenesis researchers changed the agent into something at once more benign and more useful for TB control.
Active against latent TB — maybe
Its activity against replicating TB bugs is only part of what makes PA-824 so interesting, though, says Stover. Potentially even more exciting is the fact that the compound appears to inhibit latent TB, at least when it’s tested in the classic laboratory model designed to induce what passes for a state of TB "latency" by throwing TB bugs into an anaerobic state.
In that regard, PA-824 looks similar to, but a lot more enticing than, its close cousin, metro nidazole (also known as Flagyl). In the same laboratory model of latency, that drug also seemed to inhibit latent TB. In animal models, however, metronidazole proved to be a bust, failing to show any activity against actively replicating TB.
In what may amount to no more than a bizarre but entertaining footnote, PA-824 also has been linked to "extremophiles," a category of critter that might be described as the snow-boarders and bungee-jumpers of the bacterial microcosm.
Certain extremophiles (such as the hardy organisms that flourish in deep-sea vents) possess a co-factor known as F420, Stover says; this co-factor, it turns out, is exactly what is required to activate PA-824. The link provides a tantalizing hint as to how the compound might operate against TB mycobacteria that subsist in an anaerobic state, he says.
The last time a truly novel class of compounds was introduced against TB was in 1966, when rifamycin was approved for treatment of TB. Rifamycin’s derivatives include rifapentine and rifabutin. Derivatives of drugs originally developed for use as anti-bacterials also have been developed, including quinolones such as levofloxacin.
Whatever else their activity may include, it seems certain that NAPS target some piece of the TB cell wall, Stover says. The TB cell envelope, of course, presents a formidable barrier to anti-TB drugs. Certain of its components are targeted by both isoniazid and ethambutol, which inhibit essential enzymatic processes.
As for NAPS, they appear to affect a step in the production of mycolic acids, which make up the single largest component of the cell envelope, forming a pseudo outer membrane.
"At about the same time you see the effects of lipid biosynthesis, there’s a brief stimulation of protein synthesis, too, as if the cell were trying to counteract something," Stover explains. What’s not yet understood is whether the drug’s inhibitory effects on TB derive from its impact on the synthesis of proteins, of lipids, or of both, he adds.
In animal tests, PA-824 has performed stunningly well, combining powerful efficacy with extremely low toxicity, he says. Toxicity is so far from being a problem that "we literally cannot find a toxic dose," he adds. A trial testing the potential effects of PA-824 against latent TB ("whatever that means," says Stover) would be extremely difficult to devise, of course; but the notion that the agent might be active against latent TB means it could be incredibly effective in mopping up infections.
PA-824’s star qualities notwithstanding, though, Stover says he is waiting for a deep-pocketed investor willing to sink big money into the drug’s further development. As far as PathoGenesis is concerned, PA-824’s position for now is "pretty far back in the queue," he says.
"We’re a small outfit. We simply don’t have the bandwidth to go ahead with the expensive trials in larger animals that need to be done now."
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