Thursday, December 19, 2013

Fighting tuberculosis


      A few posts back, I was discussing about the problems associated with tuberculosis (Link) and how scientists have come up with a novel strategy of attacking ATP pathways. The need for an effective drug is reflected in the rapid FDA approval of Bedaquiline (diarylquinoline anti-tuberculosis drug). As a matter of fact we badly need a Anti-tuberculosis drug. The second aspect of tuberculosis fighting is vaccine. BCG vaccination is faithfully given to a huge number of population, and yet TB is rampant in country like India. Indeed, BCG is reported to be the most widely used vaccine worldwide (administered to more than 4 billion individuals) with unmatched safety records. But how far has this whole scenario taken us into the fight against TB, is the question.

Photo 1: AFB (TB) in sputum sample
     A little bit into the history. The organism was discovered in 1882 by Robert Koch. Later, Albert Calmette and Camille Guérin, working at the Pasteur Institute (Lille), studying basic biology were trying to get a homogenized suspension of culture in a glycerin and potato medium. This couldn't be directly achieved. Trying a variety of chemicals they stumbled on the use of bile which incidentally impacted the virulence. Based on the research, they sub-cultured TB for about 11 years (Nearly 230 subcultures), a vaccine strain emerged which was successfully tested on a variety of animal models. Originally known as Bacille Bilie Calmette-Guerin, was latter renamed as Bacillus Calmette–Guérin (BCG). The story goes that the vaccine was first given orally by Weill-Halle assisted by Raymond Turpin, on 18 July 1921. The practice was continued for a significant longtime, before it came to the present day form.

       Most often am asked a question. What are the genetic changes in BCG vaccine strain? Wish I could give you a simple straight forward answer. Right from the start, there were different versions of BCG- such as the Copenhagen strain, Tice strain etc. The strains vary by several laboratory features, which has significant effect in vaccination outcome. We are really looking forward to a more robust vaccine.

Photo 2: Fiona Smaill and Zhou Xing
      An improvement has come in the form of immunity boosting vaccine.AdHu5Ag85A is a recombinant human type 5 adenovirus (AdHu5)–based TB vaccine that has been deigned at McMaster Lab (Link). The phase 1 study showed that administration of vaccine boosted polyfunctional CD4+ and CD8+ T cell immunity in previously BCG-vaccinated volunteers. According to the WHO, the vaccine is one of about 10 that are currently in the works worldwide. The lead author Zhou Xing comments "It’s critically important for us to push forward multiple vaccine candidates in order to determine which one will be the champion". Smaill added: "As a doctor who looks after patients who have tuberculosis, including those who are HIV infected, I realize how important it is going to be to control this infection with a good vaccine. We are probably one of a few groups in the world who are actually doing bench-to-human tuberculosis vaccine work, and we are excited to be part of this and thrilled that it started at McMaster." Source

Fig 1: Proposed model of Mycobacterial
heme uptake. Source
      The second wing of TB research is busy building antibiotics. A massive genomic, Proteomic and integrated bioinformatic approach, has suggested for lead candidates as antibiotic targets. AspS, aspartyl-tRNA synthetase, Pks13, a polyketide synthase involved in mycolic acid biosynthesis, MmpL3, a membrane transporter, and EccB3, a component of the ESX-3 type VII secretion system. Of these, MmpL3 is a component of the heme uptake system. Any microbiologist would tell you iron is a very important component of the bacteria functioning and a bacteria would go to great lengths to get it from the host (By such as producing hemolysins and subsequent extraction of iron, or by producing high affinity iron binding proteins such as enterochelisins). That is a potential target to target. A recently published science article has shown 2 compounds NITD-304 and NITD-349 (Indolcarboxamide compounds) showed promising pharmaco-kinetic, and favorable toxicological profiles in a mouse model. From the preliminary studies by Genetic and lipid profiling studies MmpL3 has been suggested as a likely candidate attacked.

      Scientists are often puzzled about the absolute dormant state that the MTB can achieve, a key reason for resistance. Though newer TB antibiotic development is focused on pathways that couldn't be shut down (Such as ATP synthesis), developing these drugs will take its own sweet time. Now answer for how has shown up in research. It is postulated that a MTB internal toxin called VapC20 (An endoribonuclease) can be switched on in presence of Antibiotics and off when antibiotics are not around. The VapC20 inhibits translation by cleavage of the Sarcin–Ricin loop (SRL) of 23S ribosomal RNA. This tops protein translation and induces dormancy. The cleavage is more of a loop structure dependent chemistry rather than sequence. The point is if we could make a chemical that can stop this process, may be we can do more with current antibiotics.

     In conclusion, we have still more a lot to research on TB. We are currently heading into a possible improvement in BCG vaccination and better antibiotic targets. Indeed basic biology of this organism is still left to be understood.
Simona luca, & Traian Mihaescu (2013). History of BCG Vaccine MAEDICA – a Journal of Clinical Medicine, 8 (1), 53-58 : PMC3749764

Behr MA (2002). BCG--different strains, different vaccines? Lancet Infectious diseases, 2 (2), 86-92. PMID: 11901655

Smaill F, Jeyanathan M, Smieja M, Medina MF, Thanthrige-Don N, Zganiacz A, Yin C, Heriazon A, Damjanovic D, Puri L, Hamid J, Xie F, Foley R, Bramson J, Gauldie J, & Xing Z (2013). A human type 5 adenovirus-based tuberculosis vaccine induces robust T cell responses in humans despite preexisting anti-adenovirus immunity. Science translational medicine, 5 (205) PMID: 24089406

Ioerger TR, O'Malley T, Liao R, Guinn KM, Hickey MJ, Mohaideen N, Murphy KC, Boshoff HI, Mizrahi V, Rubin EJ, Sassetti CM, Barry CE 3rd, Sherman DR, Parish T, & Sacchettini JC (2013). Identification of New Drug Targets and Resistance Mechanisms in Mycobacterium tuberculosis. PloS one, 8 (9) PMID: 24086479

Rao SP etal. (2013). Indolcarboxamide is a preclinical candidate for treating multidrug-resistant tuberculosis. Science translational medicine, 5 (214) PMID: 24307692

Winther KS, Brodersen DE, Brown AK, & Gerdes K (2013). VapC20 of Mycobacterium tuberculosis cleaves the Sarcin-Ricin loop of 23S rRNA. Nature communications, 4 PMID: 24225902

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