Understanding Tuberculosis and the challenges ahead


Recently, I had the opportunity to meet one of my colleagues from Sussex University whose area of expertise and research is based in tuberculosis (TB), Dr. S. Wadell. This heightened my curiosity on the disease and I wanted to know more.

Thus I have chosen the paper in Expert Opinion on Drug Discovery by Anuradha, Kumar et al. [1].

TB is caused by the bacteria Mycobacterium tuberculosis in humans and Mycobacterium bovis in cattle and badgers, where it still an area of ardent discussion and where there is still lot of work to do [2]

TB is highly likely to spread in areas of poor sanitation, poor access to drugs and where patients have to be confined; it is treated with cocktails of up-to-4 antibiotic drugs over periods of time greater than 6 months.

Far from being an under-controlled disease as I initially thought, TB bacteria still possess a threat to humans due to:

  1. The nature of bacteria: stick-shaped cell with a highly lipophilic-rich cell membrane, slow growing and highly infectious organism which has to be dealt in a controlled environment.
  2. Its physiology: present in an active/ latent form, existing in multiple physiological states (explaining the length and combination of antibacterial drugs required for an effective treatment)
  3. The lack of animal models due to the difficulty to replicate the disease as it occurs in humans.
  4. Location: the bacteria can be found intracellular (eg. Macrophages) or extracellular in granulomas; or cavities, individually or as aggregates. Adding a second cell membrane to be crossed and making drug delivery and distribution a challenge.
  5. Drug-resistance as it has followed in other bactericidal-type diseases. Sometimes appears associated to HIV infection.
  6. Difficulty to identify the biological environment, small target space and mechanism of action
  7. Traditional approaches targeting biochemical assays have failed due to screening libraries of compounds based in Lipinski’s rule of 5 with a low number of compounds meeting the clogP > 5 requirement is matched [3].

In contrast, the whole-cell screening, although more successful, has highlighted promiscuous targets like MmpL3 and QcrB alerting that the development of new drugs will have to answer the need to have  multiple-target active compounds.

The use of TB infected macrophages has been used as valid source of new inhibitors, either from synthetic origin as well as based in natural products [4] – open the door to chemicals no covered in commercial screening libraries. This approach has later derived in obtaining semi-synthetically analogues from Rifamycin, where the common structure (inside the blue box) is kept and highlighted are the modifications in Fig 1.

jose

   Fig 1 Current therapeutic drugs derived from Rifamycin family discovered in the 1950s and its semi-synthetic analogues.

The synthesis of active analogues from natural products can be challenging but it has recently highlighted some potential leads to be further investigated [5]. Therefore, new active compounds could follow from the isolation of active substances based in their physiochemical properties (eg. high lipophilicity) from sub-fractions of natural product mixtures [6].

The authors emphasise that current techniques using metabolomics and genomics could be valuable tools in the design and understanding the synthesis of new active compounds. The use of Diversity-orientated synthesis (DOS) is pointed as a way to generate and explore the untargeted chemical space [7].

Clear progress and innovation from new emerging techniques have led to a better understanding in fighting the disease. The lack of compounds with specific physicochemical properties as well as suitable animal models, how to penetrate the TB lipophilic cell membrane, shorter and more efficient patient treatments and which targets to focus on are going to be the areas where it is anticipated more researching resources will be deployed.

Blog written by Jose Gascon

References:

[1] Anuradha Kumar, Somsundaram Chettiar & Tanya Parish, Expert Opinion in Drug Discovery, 2017, Vol

12, 1, 1-4

[2] https://www.theguardian.com/science/2012/nov/11/alice-roberts-bovine-tb-badgers ;

http://www.tbfreeengland.co.uk/faqs/

[3] Koul, A et al  The challenge of new drug discovery for tuberculosis Nature, 2011, Jan 27:469

(7331):483-490. DOI:10.1038/nature09657

[4] Cragg, GM et al  Natural products: a continuing source of novel drug leads. Biochim Biophys Acta,

2013, 1830, 6, 3670-3695.  DOI:10.1016/j.bbagen.2013.02.008

[5] Mdluli, K et al   Tuberculosis drug discovery and emerging targets. Ann N Y Acad Sci, 2014, Sep;1323:

56-75. DOI:10.1111/nyas.12459

[6] Wagenaar, MM et al  Pre-fractioned microbial samples-the second generation natural products library

at Wyeth Molecules, 2008; 13, 6, 1406-1426 ;  Camp, D. et al  Drug-like properties: guiding principles

for the design of natural product libraries J. Nat. Prod, 2012, 75, 1,72-81

[7] Galloway, WR et al  Diversity-orientated synthesis as a tool for the discovery of novel biological active

small molecules. Nat Commun. 2010, 2, 1, 80

 

 

 

 

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