Mycobacterium tuberculosis, the bacterium that causes tuberculosis (TB), had better watch its back: Its days are numbered.
Scientists have been working on a way to kill the TB bacterium for over a century. A major advance has finally been made, one that could eventually cure this persistent illness once and for all. The key is a novel approach to TB therapy, one that targets several of its vulnerabilities all at once.
An international team of researchers, led by Pooja Arora of the (Indian) National Institute of Immunology in New Delhi, has discovered a class of proteins called fatty acyl-AMP ligases (FAALs) that help the bacterium with a crucial task: making lipids.
Lipids are fats that some cells attach to their cell surfaces to form a waxy coat. The molecules can have a variety of functions, but Mycobacterium tuberculosis takes advantage of its lipid coat for a particularly sneaky trick: to avoid detection by immune cells. This makes tuberculosis a difficult disease to treat and cure.
"Since FAALs are crucial [to the creation of the proper surface lipids], we have designed inhibitors that can simultaneously disrupt multiple pathways," Rajesh Gokhale, a Howard Hughes Medical Institute international scholar with the group, said.
Arora, Gokhale and colleagues have helped make great strides in the epic battle against tuberculosis. Perhaps they have more inspiration than the average person: Although tuberculosis is a worldwide problem, it is especially prominent in the team's native India, where each day 1,000 people die from the disease.
Unfortunately, although there are currently several drugs that combat the illness, no one drug itself is a wholly effective treatment. Patients must take a cocktail of four different drugs everyday for six to nine months, lest the bacterium develop resistance to the treatment.
The reason this combination of drugs is needed is that each drug is only able to target one part of Mycobacterium tuberculosis at a time. But to attack such a pathogen, which uses myriad proteins and enzymes throughout its life, requires a better, smarter, more effective battle strategy.
The Indian group is among the increasing population of scientists and healthcare workers who are beginning to think about infectious diseases in a new way. These scientists are starting to accept the possibility of a new generation of drugs that will target multiple pathways, debilitating pathogens by knocking out several cellular processes all at once.
With more effective, multi-tasking designs, drugs will theoretically be able to combat illnesses more quickly, more reliably and more cheaply.
Arora's group and others like them still have an incredibly long road ahead of them. At present, the drug that the team has designed, which attacks Mycobacterium tuberculosis at four of the critical lipid-dependent pathways, is highly toxic and therefore unsuited for human use.
Gokahale is fully aware of this problem, and his team is diligently working towards a more feasible treatment. "We have to take [the research] further to improve molecules that could one day be used in humans," he said.
The reason for this toxicity is that the drug, designed by the team to physically match the four target enzymes so critical to the tuberculosis bacterium, meddles with the lipid-forming pathway in human cells as well. That is what makes the drug especially good at attacking the bacterium.
Unfortunately, virtually all cells use lipids of one type or another; if the drug Arora and Gokhale have created cannot specifically target the bacteria without killing or seriously disrupting the surrounding cells, it will be of limited use.
The group is realistic about the problems that face the TB research field. But with a shift in thinking about how drugs should work, promising treatments are emerging for the first time in a long while.
