Tuberculosis Control: the Relevance of Classic Principles in an Era of Acquired lmmunodeficiency Syndrome and Multidrug Resistance

Kaye, Katherine; Frieden, Thomas R.

doi:10.1093/oxfordjournals.epirev.a017916

Cited by 46 publications

(28 citation statements)

References 53 publications

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“…Not only does the World Health Organization estimate that TB is responsible for nearly 2 million deaths each year and that a third of the global population is infected with M. tuberculosis (Dye, 2006), but recently the emergence of MDR-TB (Kaye & Frieden, 1996) and XDR-TB (Centers for Disease Control and Prevention, 2006) has come to the fore; an untreatable epidemic of XDR-TB cannot be excluded. In this worrying climate, the need for the discovery and characterization of key enzymes involved in essential mycobacterial biosynthetic pathways towards the definition of novel targets for chemical intervention and the testing of novel classes of potential inhibitors is apparent.…”

Section: Discussionmentioning

confidence: 99%

“…TB control has been made difficult in recent years by the apparent synergy between the causative agent, Mycobacterium tuberculosis, and HIV (Paolo & Nosanchuk, 2004). In addition, the length and complexity of current TB treatment regimens results in poor patient compliance, a major contributing factor in the emergence of multi-drug-resistant TB (MDR-TB) (Kaye & Frieden, 1996) and extensively drug-resistant (XDR)-TB (Centers for Disease Control and Prevention, 2006). Given this backdrop, the effective control of TB requires the identification of new drug targets and the discovery of novel drugs.…”

Section: Introductionmentioning

confidence: 99%

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Flavonoid inhibitors as novel antimycobacterial agents targeting Rv0636, a putative dehydratase enzyme involved in Mycobacterium tuberculosis fatty acid synthase II

et al. 2007

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Flavonoids comprise a large group of bioactive polyphenolic plant secondary metabolites. Several of these possess potent in vivo activity against Escherichia coli and Plasmodium falciparum, targeting enzymes involved in fatty acid biosynthesis, such as enoyl-ACP-reductase, b-ketoacyl-ACP reductase and b-hydroxyacyl-ACP dehydratase. Herein, we report that butein, isoliquirtigenin, 2,29,49-trihydroxychalcone and fisetin inhibit the growth of Mycobacterium bovis BCG. Furthermore, in vitro inhibition of the mycolic-acid-producing fatty acid synthase II (FAS-II) of Mycobacterium smegmatis suggests a mode of action related to those observed in E. coli and P. falciparum. Through a bioinformatic approach, we have established the product of Rv0636 as a candidate for the unknown mycobacterial dehydratase, and its overexpression in M. bovis BCG conferred resistance to growth inhibition by butein and isoliquirtigenin, and relieved inhibition of fatty acid and mycolic acid biosynthesis in vivo. Furthermore, after overexpression of Rv0636 in M. smegmatis, FAS-II was less sensitive to these inhibitors in vitro. Overall, the data suggest that these flavonoids are inhibitors of mycobacterial FAS-II and in particular Rv0636, which represents a strong candidate for the b-hydroxyacyl-ACP dehydratase enzyme of M. tuberculosis FAS-II.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Flavonoid inhibitors as novel antimycobacterial agents targeting Rv0636, a putative dehydratase enzyme involved in Mycobacterium tuberculosis fatty acid synthase II

et al. 2007

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“…There is one death from TB every 15 s (over two million per year), and eight million people develop TB every year. Without treatment, up to 60% of people with the disease will die (152). Essentially all these cases are in the Third World (318a), reflecting the poverty and the lack of healthy living conditions and adequate medical care (301).…”

Section: History Of Tuberculosismentioning

confidence: 99%

Mycobacterium tuberculosisPathogenesis and Molecular Determinants of Virulence

2003

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Tuberculosis (TB), one of the oldest known human diseases. is still is one of the major causes of mortality, since two million people die each year from this malady. TB has many manifestations, affecting bone, the central nervous system, and many other organ systems, but it is primarily a pulmonary disease that is initiated by the deposition of Mycobacterium tuberculosis, contained in aerosol droplets, onto lung alveolar surfaces. From this point, the progression of the disease can have several outcomes, determined largely by the response of the host immune system. The efficacy of this response is affected by intrinsic factors such as the genetics of the immune system as well as extrinsic factors, e.g., insults to the immune system and the nutritional and physiological state of the host. In addition, the pathogen may play a role in disease progression since some M. tuberculosis strains are reportedly more virulent than others, as defined by increased transmissibility as well as being associated with higher morbidity and mortality in infected individuals. Despite the widespread use of an attenuated live vaccine and several antibiotics, there is more TB than ever before, requiring new vaccines and drugs and more specific and rapid diagnostics. Researchers are utilizing information obtained from the complete sequence of the M. tuberculosis genome and from new genetic and physiological methods to identify targets in M. tuberculosis that will aid in the development of these sorely needed antitubercular agents

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“…The spread of TB has been facilitated in recent years due to the susceptibility of HIV-infected individuals to Mycobacterium tuberculosis, the aetiological agent of TB (Paolo & Nosanchuk, 2004). The problem has also been compounded by the emergence of multi-drug-resistant TB (MDR-TB) (Kaye & Frieden, 1996) and extensively drugresistant (XDR)-TB strains (Wright et al, 2006). M. tuberculosis and other mycobacteria have a distinct cell wall which has a lipid-rich outer layer that is highly impermeable (Minnikin, 1982).…”

Section: Introductionmentioning

confidence: 99%

Identification of the dehydratase component of the mycobacterial mycolic acid-synthesizing fatty acid synthase-II complex

et al. 2007

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Mycolic acids are vital components of the Mycobacterium tuberculosis cell wall and are essential for survival. While most components of the fatty acid synthase-II (FAS-II) enzymic machinery that synthesizes these long chain a-alkyl, b-hydroxy fatty acids have been identified, the gene encoding the b-hydroxyacyl-acyl carrier protein (ACP) dehydratase activity has remained elusive. Recent bioinformatics-based studies and drug inhibition experiments have identified the M. tuberculosis gene Rv0636 as a promising candidate for this role. Using a recently described, specialized transduction-based genetic tool we now demonstrate that MSMEG1341, the Mycobacterium smegmatis homologue of Rv0636, is an essential gene; null mutants of the gene could only be generated in a merodiploid strain which contained a second integrated acetamide-inducible copy of MSMEG1341. Growth of the conditional mutant in the absence of acetamide resulted in loss of mycolic acid biosynthesis and eventually loss of viability due to cell lysis. Null MSMEG1341 mutants could also be generated in a M. smegmatis strain containing an integrated copy of Rv0636, indicating that Rv0636 was the functional counterpart of MSMEG1341 in M. tuberculosis. Our results demonstrate that MSMEG1341 is an essential gene involved in mycolic acid biosynthesis and encodes the FAS-II b-hydroxyacyl-ACP dehydratase.

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Tuberculosis Control: the Relevance of Classic Principles in an Era of Acquired lmmunodeficiency Syndrome and Multidrug Resistance

Cited by 46 publications

References 53 publications

Flavonoid inhibitors as novel antimycobacterial agents targeting Rv0636, a putative dehydratase enzyme involved in Mycobacterium tuberculosis fatty acid synthase II

Flavonoid inhibitors as novel antimycobacterial agents targeting Rv0636, a putative dehydratase enzyme involved in Mycobacterium tuberculosis fatty acid synthase II

Mycobacterium tuberculosisPathogenesis and Molecular Determinants of Virulence

Identification of the dehydratase component of the mycobacterial mycolic acid-synthesizing fatty acid synthase-II complex

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