Current Status and Research Strategies in Tuberculosis Drug Development

Dover, Lynn G.; Coxon, Geoffrey D.

doi:10.1021/jm200305q

Cited by 109 publications

(61 citation statements)

References 60 publications

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“…Nearly nine million new cases are estimated each year, two million of them being fatal due to the increment of multidrug resistant Tb [2,3]. The eradication of Tb is difficult since MTb lipidic envelope confers impermeability to antibiotics and ability to withstand unfavorable conditions [1,3,4].…”

Section: Introductionmentioning

confidence: 99%

Interplay of mycolic acids, antimycobacterial compounds and pulmonary surfactant membrane: A biophysical approach to disease

Pinheiro

Giner‐Casares

Lúcio

et al. 2013

Biochimica et Biophysica Acta (BBA) - Biomembranes

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This work focuses on the interaction of mycolic acids (MAs) and two antimycobacterial compounds (Rifabutin and N'-acetyl-Rifabutin) at the pulmonary membrane level to convey a biophysical perspective of their role in disease. For this purpose, accurate biophysical techniques (Langmuir isotherms, Brewster angle microscopy, and polarization-modulation infrared reflection spectroscopy) and lipid model systems were used to mimic biomembranes: MAs mimic bacterial lipids of the Mycobacterium tuberculosis (MTb) membrane, whereas Curosurf® was used as the human pulmonary surfactant (PS) membrane model. The results obtained show that high quantities of MAs are responsible for significant changes on PS biophysical properties. At the dynamic inspiratory surface tension, high amounts of MAs decrease the order of the lipid monolayer, which appears to be a concentration dependent effect. These results suggest that the amount of MAs might play a critical role in the initial access of the bacteria to their targets. Both molecules also interact with the PS monolayer at the dynamic inspiratory surface. However, in the presence of higher amounts of MAs, both compounds improve the phospholipid packing and, therefore, the order of the lipid surfactant monolayer. In summary, this work discloses the putative protective effects of antimycobacterial compounds against the MAs induced biophysical impairment of PS lipid monolayers. These protective effects are most of the times overlooked, but can constitute an additional therapeutic value in the treatment of pulmonary tuberculosis (Tb) and may provide significant insights for the design of new and more efficient anti-Tb drugs based on their behavior as membrane ordering agents.

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Section: Introductionmentioning

confidence: 99%

Interplay of mycolic acids, antimycobacterial compounds and pulmonary surfactant membrane: A biophysical approach to disease

Pinheiro

Giner‐Casares

Lúcio

et al. 2013

Biochimica et Biophysica Acta (BBA) - Biomembranes

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“…Tuberculosis (TB), 3 a disease that remains a significant worldwide health threat, is caused by infection with Mycobacterium tuberculosis. In common with all mycobacteria, M. tuberculosis possesses a unique glycolipid-rich cell wall structure that provides substantial protection from the environment, including preventing the passage of antibiotics into the organism (1).…”

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confidence: 99%

“…In common with all mycobacteria, M. tuberculosis possesses a unique glycolipid-rich cell wall structure that provides substantial protection from the environment, including preventing the passage of antibiotics into the organism (1). The standard TB drug regimen (2) therefore involves multiple antibiotics, including some that target cell wall biosynthesis and others that have intracellular targets (3). Concerns about drug resistance (4) have led to heightened interest in identifying novel therapeutic agents and developing a more detailed understanding of mycobacterial biochemical pathways to facilitate this task.…”

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confidence: 99%

Tetrameric Structure of the GlfT2 Galactofuranosyltransferase Reveals a Scaffold for the Assembly of Mycobacterial Arabinogalactan

Wheatley

Zheng

Richards

et al. 2012

Journal of Biological Chemistry

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Background: GlfT2 is a bifunctional galactofuranosyltransferase essential for mycobacterial cell wall biosynthesis. Results: Crystal structures of free and UDP-bound GlfT2, along with mutagenesis and kinetic studies, reveal novel details underlying substrate binding and catalysis. Conclusion:The homotetrameric architecture, distinctive nucleotide-binding site, and unprecedented structural features underlying the bifunctional polymerase activity of GlfT2 are revealed. Significance: Novel insights into polymerizing glycosyltransferases and the design of anti-mycobacterial therapeutics are obtained.

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“…Multidrug resistant TB (MDR TB) is de ned by resistance to at least isoniazid (1) and rifampicin (2), and requires 18 months therapy with the remaining rst line drugs in combination with second line drugs (Figure 2), which are generally more toxic and expensive. Extensively drug resistant TB (XDR TB) is caused by Mtb resistant to isoniazid (1), rifampicin (2), at least one uoroquinolone (14 16), and one of the three most potent injectables such as capreomycin (7), amikacin (12), or kanamycin (13). XDR TB must be treated with even more expensive and toxic third line drugs (Figure 3), however the success rate of the treatment of XDR TB is very low.…”

Section: Tuberculosis (Tb) Caused By Mycobacterium Tuberculosismentioning

confidence: 99%

Recent Progress on the Development of Novel Antitubercular Agents from Whole-Cell Screening Hits

Yokokawa

2014

J. Synth. Org. Chem. Jpn.

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Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) continues to be a serious major global health risk. More than one third of the world s human population is infected, resulting in 1.4 2.0 million deaths per year. The rst line therapy using a multidrug regimen has existed since the 1970s, however, there has been an alarming increase in the number of patients with multi (MDR) and extensive (XDR) drug resistant TB in recent years. Hence, there is an urgent need to develop novel drugs with new mechanisms of action and new chemotypes in order to combat drug resistant TB. A target based approach to nding new anti TB agents has been widely used, however this approach has not led to the identi cation of clinical candidates. The recent trend has been to go back to whole cell screens, in which compounds are identi ed based on their anti TB activity. Consequently, various groups have reported structurally diverse active compounds against Mtb, which were originally identi ed from phenotypic screens. This review will cover recent scienti c accounts published from these groups that have described medicinal chemistry optimization studies from whole cell screening hits. In vivo pharmacokinetics and ef cacy of optimized compounds as well as their potential molecular targets will be also discussed.

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Current Status and Research Strategies in Tuberculosis Drug Development

Cited by 109 publications

References 60 publications

Interplay of mycolic acids, antimycobacterial compounds and pulmonary surfactant membrane: A biophysical approach to disease

Interplay of mycolic acids, antimycobacterial compounds and pulmonary surfactant membrane: A biophysical approach to disease

Tetrameric Structure of the GlfT2 Galactofuranosyltransferase Reveals a Scaffold for the Assembly of Mycobacterial Arabinogalactan

Recent Progress on the Development of Novel Antitubercular Agents from Whole-Cell Screening Hits

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