In antibiotics discovery, the low-hanging fruit may be gone. But Carl Nathan, chairman of the department of microbiology and immunology at Weill Cornell Medical College in New York, thinks that with a little bit of imagination, there's plenty of ways left to bite bugs back.
Current antibiotics, Nathan, told BioWorld Today, target only four types of biosynthetic processes: They interfere with the synthesis of nucleic acids, proteins, the bacterial cell wall and folate. "That leaves out wide swatches of metabolism that bacteria require to cause disease."
In the March 2008 issue of Cell Host and Microbe, senior author Nathan and his colleagues showed one example of what can result when the search is broadened: a compound that interferes with intermediary metabolism and the antioxidant defense of mycobacterium tuberculosum, specifically targeting nondividing bacteria.
Nonreplicating tuberculosis bacteria are a problem for two reasons. They remain a threat to their host during so-called latent infections, which develop into active disease in about 10 percent of cases. And given that almost a third of the world's population is infected, those 10 percent translate into a global burden of 9 million cases of active infection a year.
Less obviously, nonreplicating bacteria also are a problem in active infection. That's because even during the height of an active tuberculosis infection, "there is a small subpopulation that resists being killed" by antibiotics that target dividing cells because those cells are not, in fact, dividing, Nathan explained.
It is the nonreplicating bacteria that make it necessary for tuberculosis treatment to last six months to get the relapse rate down to 5 percent, Nathan explained. Even though most of the bacteria are dead within three days, the reservoir of nondividing bacteria remains, resistant to drugs that target cell division.
A drug that targets nonreplicating bacteria could drastically shorten the treatment time, which would improve compliance and help prevent the further spread of drug-resistant tuberculosis.
In their Cell Host and Microbe paper, Nathan and his colleagues targeted an enzyme called dihydrolipoamide acetyltransferase or DlaT, which the bacterium uses both to extract energy from nutrients and as an antioxidant defense. Researchers first infected mice and guinea pigs with tuberculosis bacteria lacking the DlaT, and found that such engineered bacteria were unable to persistently infect the animals, suggesting that DlaT is critical for infection.
The researchers used screens that tested for bactericidal activity, rather than traditional growth assays, which would be unable to identify antibiotics that work on nonreplicating bacteria. Nathan said the development of assays that can find effective antibiotics without screening for bacterial growth is itself an important aspect of his team's work. "It's terribly important that there are fresh ways to design the search," he said.
He also stressed that such fresh approaches need to be accompanied by a willingness to consider their results, saying that antibiotics discovery has been in some ways a victim of its own success. One argument from industry against developing drugs based on metabolism and antioxidant defenses, he said, was that they are shared between bacteria and their hosts. But "that reasoning has always struck me as disingenuous," since current targets such as ribosomes also are shared between bacteria and their host, he added.
By combining such screens with chemical optimization, they were able to identify a compound that killed nondividing tuberculosis bacteria within macrophages, immune system cells that are a major hideout for latent tuberculosis bacteria. Nathan said that his team has since identified several other compounds that kill nondividing M. tuberculosis, suggesting that the overall approach could yield a good number of novel compounds. And while he cautioned that not every compound that will kill a bacterium makes a good drug, Nathan said that the work had shown that "at least conceptually, nondividing bacteria have vulnerabilities that we can exploit. . . . We just started, and it worked beautifully."
Almost a third of the world's population is infected with tuberculosis, and multidrug-resistant tuberculosis is rapidly becoming a problem of the good old days before extremely drug-resistant tuberculosis. But if part of Nathan's goal is to broaden the range of what are considered viable approaches to antibacterial drug development, his vision of what such antibacterial drug development could achieve is at least equally expansive.
Tuberculosis "could be eradicated in theory," because it has no hosts other than humans, he said. And "while that goal might seem totally out of reach, the goal of drastically reducing new infections in a given community is reasonable in my opinion." By combining new drugs with public health measures, he said, latent infection could be reduced from a third to less than 1 percent of a community. And if it happens in a sufficient number of communities, "it might eventually be possible to approach eradication."