TUBERCULOSIS:

Tuberculosis may be defeated through a new therapeutic approach, based on countering the microbial stress response and restoring normal metabolism.

Antibiotic resistance is the phenomenon in which microbes develop the capacity to neutralize drugs that would otherwise damage or kill them. It's rapidly becoming a serious global health problem.

Many dangerous diseases were once major killers, but subsequently became treatable with drugs. Some of these diseases are once again becoming lethal due to antibiotic resistance.

A well-known example is tuberculosis, a disease that has been infecting humans for many thousands of years. Never caught it, you say? There's a good chance you have; roughly one-third of the world has been infected with the causative bacterium, Mycobacterium tuberculosis.

Infection doesn't usually cause obvious symptoms, but it can become symptomatic and deadly, especially in people with weak immune systems (such as the young, old, and HIV-infected). Tuberculosis kills approximately two million people every year.

The challenge of treating tuberculosis.

Effective treatment for tuberculosis first requires an accurate, definitive diagnosis. Unfortunately, this is a slow process; weeks or months are commonly required for the requisite cell cultures.

Novel diagnostic approaches such as mass spectrometry may considerably cut down diagnosis time. However, after diagnosis, the real microbe-defeating effort has just begun.

Inherent drug resistance is a big problem with tuberculosis, as is additional antibiotic resistance complications. Recent research shows that some drug combinations can selectively kill drug-resistant bacteria, but this discovery by itself is unlikely to defeat Mycobacterium tuberculosis.

A hint as to why tuberculosis is so difficult to treat is that although Mycobacterium tuberculosis is readily killed when the bacteria are grown in a cell culture, it's notoriously difficult to kill in a living person. Something about it growing in a person hinders treatment.

Why not just develop fundamentally new drugs? Possibly the biggest reason why this is an unattractive option is that developing new drugs is often incredibly expensive, although re-using old drugs for new purposes has the potential to sometimes greatly reduce this cost.

Another reason, already mentioned, is that drugs are slow to work against tuberculosis (at least six months) in medically-relevant settings (i.e. real people). Scientists must figure out why this is, and how to counter the effect, if Mycobacterium tuberculosis is to be permanently treatable if not completely eradicated.

Christopher Sassetti (University of Massachusetts, United States) and coworkers have made an important contribution to this effort. They have discovered how to manipulate microbial metabolic pathways to enhance the sensitivity of Mycobacterium tuberculosis to antibiotics.

Defeating tuberculosis.

Mycobacterium tuberculosis is commonly thought to resist antibiotics by slowing down metabolism (bacteria that replicate quickly are the common targets of antibiotics). The underlying premise of Sassetti and coworkers' research is that drugs which speed up microbial metabolism may erode antibiotic resistance.

They identified 34 genes responsible for the bacterium's growth in oxygen-deprived (stress) conditions, some of which are involved in triacylglycerol production. Sassetti and coworkers' research, as well as that of other scientists, has shown that triacylglycerol is over-produced by Mycobacterium tuberculosis in response to numerous stress conditions (oxygen deprivation, acidic pH, and iron deficiency).

They next found that triacylglycerol production slows down metabolism. It does so because triacylglycerol synthesis uses up acetyl CoA, an important biomolecule in the tricarboxylic acid cycle (a central metabolic pathway).

To summarize, Mycobacterium tuberculosis over-produces triacylglycerol, which slows down metabolism and enhances antibiotic resistance. Therefore, slowing down triacylglycerol over-production may be a method of hindering antibiotic resistance.

The scientists found that genetically altered Mycobacterium tuberculosis, such that triacylglycerol over-production was hindered, were partially susceptible to a variety of antibiotics: isoniazid, streptomycin, ciprofloxacin, and ethambutol. The same general resistance-negating effect was seen in infected mice, even though microbial metabolism didn't seem to be affected much.

After 28 days of antibiotic treatment, mice infected with normal Mycobacterium tuberculosis reduced their bacterial levels by a factor of 20. In contrast, mice infected with bacteria that were genetically altered to hinder triacylglycerol over-production had bacterial levels drop below the detection limit.

To summarize, enhancing the metabolism of Mycobacterium tuberculosis enhances its susceptibility to antibiotics. Mice treated with this concept in mind were essentially cured of the infection within one month.

Future directions.

Further research is necessary to determine which aspects of Mycobacterium tuberculosis metabolism are affected by different stress conditions, and therefore may offer additional avenues of attack against drug resistance. In the meantime, scientists should focus their efforts on the pathway described in Sassetti and coworkers' research, with the goal of pharmaceutically targeting the microbes' own metabolism to enhance antibiotic susceptibility.

NOTE: The scientists' research was funded by the National Institutes of Health, the Howard Hughes Medical Institute, and the Heiser Foundation.

Baek, S., Li, A., & Sassetti, C. (2011). Metabolic Regulation of Mycobacterial Growth and Antibiotic Sensitivity PLoS Biology, 9 (5) DOI: 10.1371/journal.pbio.1001065