New research suggests the bacteria that cause tuberculosis (TB) alter their metabolism to combat exposure to antimicrobials, and new drugs could neutralize the metabolic "escape pathways" to shorten the duration of therapy.
The findings, published recently in Antimicrobial Agents and Chemotherapy, are hailed as important because the respiratory disease kills nearly 2 million people a year worldwide, and its long treatment regimen leads to poor compliance and, in turn, drug-resistant germs.
About one-third of the global population is infected with Mycobacterium tuberculosis, or Mtb, though only a small percentage will develop TB.
For those who do, treatment is basically the same now as it was a half-century ago: taking a combination of drugs for six months, because the germs do not die easily.
Luiz Bermudez and collaborators at the veterinary college of Oregon State University (OSU), as well as researchers at OSU's colleges of science and pharmacy and Oregon Health & Science University, took a biology-driven approach to learn how Mtb prolongs survival following exposure to bactericidal concentrations of antimicrobials.
In an effort to investigate how the bacteria reacted to each class of anti-TB drug with the goal of making headway toward developing a more-reasoned combination therapy, the researchers studied the proteomic responses of the bacteria to five compounds, namely isoniazid, rifampicin, moxifloxacin, mefloquine and bedaquiline, and discovered escape pathways and enzymes associated with changes in metabolic state.
"When we looked at the enzymes carefully, we realized the enzymes being synthesized by the bacteria were enzymes connecting several different metabolic pathways," Bermudez said.
"Then we came up with the idea that maybe what the bacteria were trying to do, in the presence of a bactericidal compound that was threatening their way of living, was use other ways to survive. One of the things we saw, for example, was a shift to an anaerobic metabolism, which makes a lot of drugs inactive and incapable of killing bacteria."
Using a combination of drugs to treat TB arose as an attempt to prevent antibiotic resistance, he noted.
"But the antibiotics used were never a rational combination of drugs and in some cases they could antagonize each other," he was quoted as saying in a news release from OSU.
"If we can use another compound that inhibits bacteria from shifting metabolic pathways, then we get a more reliable and desirable synergy of therapy. That might have a significant impact on reducing the time needed for therapy and improving compliance and, consequently, reducing the emergence of resistance."
"The gene inactivation of some of these enzymes results in improved drug efficacy against Mtb," he said. "The identified proteins may provide powerful targets for development of synergistic drugs aimed to accelerate bacterial killing."
The researchers said that anyone who's ever had trouble sticking with a 10-day antibiotic regimen for an ear infection can understand the hurdles in taking multiple medicines for a couple of dozen weeks, especially given the numerous side effects of the TB drugs.
Another compliance issue is that TB is particularly prevalent in impoverished countries in which patients often live great distances from pharmacies and other medical facilities.
"Because of problems with compliance, you have resistance becoming more and more of an issue," said Bermudez.
