Recent Advances in Antituberculous Drug Development and Novel Drug Targets

Haruaki Tomioka, PhD; Yutaka Tatano, PhD; Ko Yasumoto, PhD; Toshiaki Shimizu, PhD

Disclosures

Expert Rev Resp Med. 2008;2(4):455-471. 

In This Article

Drug Targets in Persistent & Latent MTB Infection

The identification of the mechanisms by which MTB persists within its hosts will allow the design of new types of anti-tubercular drugs that specifically target persistent tubercle bacilli, defined as MTB organisms that have managed to tolerate drug treatment, presumably through an ability to suspend replication, and whose replication resumes soon after the drug has been removed. The use of such anti-TB drugs active against persistent MTB organisms makes it possible to shorten the time periods required for anti-TB chemotherapy without increasing the relapse rate. Moreover, there are approximately 1.7 billion people in the world who have been infected at some point with tubercle bacilli and, in such persons, MTB organisms are surviving as dormant MTB, defined as MTB organisms as they exist in a latent and asymptomatic state where bacterial growth is undetectable until the host's immune system has been compromised. Thus, the prophylactic administration of anti-tuberculous drugs effective against dormant MTB is efficacious in decreasing the incidence of TB reactivation in high-risk individuals, such as patients with HIV infection. The following gene targets are promising in persistent and latent MTB infection.

First, MTB organisms in persistent stages show a metabolic shift in which bacterial glycolysis is decreased and glyoxylate shunt is upregulated, allowing the bacteria to use the C2 substrate generated by the ß-oxidation of fatty acids. Isocitrate lyase (Icl), which is a key enzyme in the glyoxylate cycle and is essential as an anapleurotic enzyme for growth using acetate and certain fatty acids as a carbon source, is upregulated in MTB organisms that are exposed to anaerobic conditions and are in the stationary phase, or growing inside macrophages.[42,43,44,45] Indeed, an icl mutant of MTB reportedly replicated invivo identically to wild-type organisms during the first 2weeks of infection, but was steadily eliminated after the onset of host acquired cellular immunity to MTB antigens.[46] This indicates that the icl gene plays a crucial role in the persistence of MTB organisms in vivo. Indeed, Icl is necessary for the survival of MTB in activated macrophages.[46] Since human beings have no functional glyoxylate shunt, the Icl protein will serve as a promising drug target. In addition, a second isocitrate lyase encoded by the aceA gene and malate synthase (the second enzyme of the glyoxylate shunt) encoded by the glcB gene are thought to be required for the persistence of MTB.[14,43,47] Thus, these enzymes are also attractive targets for new anti-TB drugs. However, it should also be noted that comprehensive anti-TB drug screening based on these drug targets is not easy; ingenious assay systems to assess the viability of persisting/dormant MTB organisms are needed. Indeed, HTS applications of a library of more than 1 million organic molecules for promising anti-MTB drugs, based on certain drug targets, such as Icl and malate synthase (GlcB), met with little success, because of the difficulty in whole-cell screening and for other reasons. In this context, it has recently been reported that the low-oxygen-recovery assay is very useful for the HTS of compounds against nonreplicating MTB.[48]

Second, Murphy et al.[49] recently identified promising gene targets via meta-analysis of multiple, published databases based on gene-expression DNA microarray experiments that modeled MTB infection leading to and including a dormant state.[50,51,52,53,54,55] According to their analysis, the bacterial response to in vitro stress due to hypoxia, starvation and intramacrophage exposure to bactericidal molecules, such as reactive nitrogen intermediates (RNIs) and ROIs, and in vivo stress encountered in the granuloma milieu during infection in mice, included the upregulation of genes controlled by the devR gene (also known as dosR), downregulation of protein and ATP synthesis and adaptation of two-carbon metabolism to the hypoxic and nutrient-limited environments of granulomas.[49] Notably, the 53 genes regulated by devR are upregulated in response to bacterial dormancy-related stress, and include 11 genes involved in carbohydrate and fatty acid metabolism and eight genes involved in electron transfer.[49] Thus, the DevR protein is an important regulator of genes in response to the experimental stressors of hypoxia and nitric oxide radicals. It is therefore thought that devR is a promising gene target for anti-TB drugs. In addition, Murphy's study indicated other promising drug targets, including DevS (regulator of devR), MprA/MprB (two-component sensor kinase/transcriptional regulator), RelA (stringent response Rel protein affecting RNA polymerase and gene expression) and enzymes involved in redox balance and respiration, pantothenate, isoprene and NAD biosynthesis.[49]

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