A New Therapy for Tuberculosis

It is often tempting to abandon old ways for glamorous new ones. Such is certainly the case for antibiotic development. However, a recent study by Andries and colleagues1 shows that established methods, enhanced by modern techniques, can be used to generate exciting results.

Traditionally, we have identified antibiotics by looking for compounds that block microbial growth. Since many pathogens can easily be cultured, it is a straightforward matter to screen large numbers of compounds in order to identify any that inhibit the growth of these pathogens. This strategy has several advantages. First, there is no need to guess which microbial structure will make a good drug target. The fact that a compound works at all provides strong evidence that its target is required for growth - at least under the conditions used for screening. Second, any identified compound must have the capacity to cross the cell wall and bypass potential microbial defenses, such as degradative enzymes and efflux pumps. Third, this type of assay can be used to identify prodrugs (those that are active only after modification by the microbe) that are otherwise not easy to find.

However, this approach also has a substantial disadvantage. Although active compounds can be identified, their target remains unknown. This creates a very practical problem. The so-called hit compounds found during initial screening can rarely be used therapeutically because they seldom kill microbes at concentrations achievable in vivo. Furthermore, many will be toxic or have poor pharmacokinetic properties. To avoid these problems, hit compounds undergo multiple rounds of chemical modification. Knowing the target greatly aids this process by allowing both the use of comparatively simple in vitro assays and the differentiation of the target from other host structures.

Unfortunately, it can be quite difficult to identify the target of an antibiotic. In some bacterial strains, modern genetic methods can help, but they are not a panacea: the targets of some antibiotics that have been available for years remain unknown. Thus, many approaches to screening start with a search for biochemical inhibitors of potential targets and then focus on those that inhibit microbial growth.

Andries et al. looked for compounds that could inhibit the growth of either specific bacterial species or those that are more broadly active. They started with a library of diarylquinoline compounds, a class distantly related to drugs that include fluoroquinolone antibiotics and the antimalarial drug mefloquine. They found several candidates that inhibited the growth of both Mycobacterium smegmatis (a rapidly growing, avirulent species) and M. tuberculosis. Some of these compounds were active at very low concentrations and met with spontaneous resistance infrequently.

To pinpoint the target of one compound, Andries et al. used a method that would have been inconceivable only a few years ago. They selected independent M. smegmatis and M. tuberculosis variants that were resistant to a candidate compound (currently called R207910). Instead of relying on traditional genetic methods, they sequenced the entire genomes of three resistant strains (and, in the case of M. smegmatis, the drug-sensitive parental strain). These strains had a number of genetic changes in relation to their parental strains. Most changes were scattered throughout the genome. However, all three strains carried mutations in a gene encoding part of the F0 subunit of ATP synthase, the critical protein complex required to synthesize ATP. Indeed, introducing a copy of the mutant gene into an otherwise drug-sensitive strain of M. smegmatis rendered the strain resistant. This finding represents very strong evidence that R207910 blocks the synthesis of ATP, a completely novel antibiotic activity. However, even though the F0 ATP synthase is found in all bacteria, R207910 has limited activity against other bacterial species.

Figure 1. Use of R207910 in an Antituberculosis Regimen.

A recent study by Andries and colleagues1 proposes a new compound, called R207910, as a potential treatment for Mycobacterium tuberculosis. They tested the compound in mice that had been infected intravenously with M. tuberculosis. After waiting 12 days to allow the bacteria to grow, they divided the mice into two groups and treated them with a three-drug regimen containing either isoniazid or R207910. When the mice were killed after two months of treatment, the animals that had received the regimen containing R207910 had no detectable microorganisms.

The identification of a promising new compound for the treatment of tuberculosis is exciting. Current regimens require treatment with multiple drugs (including isoniazid, rifampin, pyrazinamide, and ethambutol) for several months. It is difficult to comply with this complex and prolonged regimen, and consequently, there is a substantial rate of treatment failure, even among patients with drug-sensitive disease. Thus, the availability of a more potent antibiotic that could clear infection more rapidly would be very valuable.

Andries et al. did much more than simply identify the compound and its target. They showed that this compound is active against a number of drug-resistant strains of M. tuberculosis. They found that R207910 is not toxic in mice and can eradicate the infection.

In fact, a three-drug regimen that included R207910 in place of isoniazid cleared the infection more rapidly and effectively than did the traditional combination (Figure 1). Initial data suggest that the agent has no serious short-term effects that would create barriers to its use in humans.

None of these findings guarantee that R207910 will be a successful antibiotic. Like any drug, it could turn out to be toxic during long-term use.

M. tuberculosis organisms seem to enter an antibiotic-tolerant state - an event that is probably more frequent in human infections than in mouse infections - and we do not yet know how effectively R207910 will deal with this problem. Nevertheless, this is clearly the most promising new antituberculosis agent that has been identified in many years.

Submitted By
Eric j. Rubin, M.D., Ph.D.
From the School of Public Health, Harvard University, Boston.

Similar of A New Therapy for Tuberculosis

Tuberculosis

Tuberculosis, commonly referred to as TB, is a chronic bacterial infection that can spread through the lymph nodes and bloodstream to any organ in your body

Tuberculosis in Alternative Medicine

Tuberculosis (TB) is a bacterial disease that mainly affects the lungs. In 15% of patients it affects other areas, causing swollen lymph nodes, pleurisy (

Diseases Resembling Tuberculosis

Many types of mycobacteria exist; many can cause infections that produce symptoms similar to tuberculosis. The most common are a group known as Mycobacterium

Monitoring Long-Term Drug Treatment

If you are undergoing long-term drug treatment for a medical problem, yoshould always take the correct amount of medication at the correct times (as

Prevention & Control of Tuberculosis

National TB Control Programme 1. National TB Control Programme: The NTP is an approach within the national health system to control TB. 2.The Aims of the NTP:

Antibiotic Choices For Treating Acute Otitis Media

Standard Antibiotics for Acute Otitis Media (AOM) While many different antibiotics may be used to effectively treat otitis media, the physician needs to

Stem Cells: Hidden Key to Growth of Tumors?

Stem cells have become famous for their ability to heal, spurring hopes that they might one day cure Parkinson's disease, spinal cord injuries and a wide

Topics:

Comments

Post new comment