Tuberculosis drug development: challenges, pitfalls and a light at the end of the tunnel?

Tuberculosis drug development has seen an increase in research activity in recent years. Here, the challenges, pitfalls and future perspective of this ever changing landscape are discussed.

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Mar 20, 2018
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Gemma Nixon1 
1Department of Chemistry, University of Liverpool 
gnixon@liverpool.ac.uk

TB facts | An ideal drug? | Challenges | Recent developments |
| Future perspectives | References |

TB facts and current drugs

In 2016, tuberculosis (TB) infected 10.4 million people globally resulting in an estimated 1.3 million deaths.[1] The continued reporting of cases of multi-drug resistant (MDR) and extensively drug resistant (XDR) TB highlight the urgent need for new drug treatments targeting the disease.[2] Current first line drugs for TB were developed in 1952–1966.  Shortcomings of these drugs include long treatment regimens – typically six to nine months – leading to patient noncompliance, adverse drug-drug interactions with anti-HIV drugs (HIV/AIDS is a common co-infection) and limited or no activity against MDR and XDR Mycobacterium tuberculosis (Mtb).[3]

From 1966–2012 there were no new TB drugs approved for clinical use. In 2012, bedaquiline (Figure 1)[4,5] was approved by the FDA for the treatment of TB, followed by delamanid in 2014.[6,7] Their approval is currently only for MDR in cases where established treatments have failed.[8] Whilst this is undoubtedly progress, there are still significant improvements to be made in the treatment of tuberculosis.

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An ideal TB drug?

Having highlighted the need for TB drug development programs, what are we trying to achieve with any new treatment? 

There is clearly a driving force to shorten and simplify treatment to improve patient compliance, in addition to a requirement for activity against drug persistent Mtb populations, for drugs to be effective against MDR- and XDR-TB and for novel modes of action to circumvent resistance. Co-administration with antiretroviral therapies and, as such, no cytochrome P450-mediated drug-drug interactions is essential, as is an excellent safety and tolerability profile, oral bioavailability and a low cost of goods.

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Challenges and pitfalls

In addition to the high attrition rates, long timelines and huge costs associated with all drug development pipelines, TB drug development faces many unique, disease-specific challenges. Earlier discovery stages are hampered by additional costs and training associated with the specialist containment facilities required for Mtb’s category three pathogen classification. Surrogate pathogens such as Mycobacterium smegmatis are often used, but can give misleading results in the establishment of early structure activity relationship trends. A standard replicating TB assay also does not represent the physiology of tuberculosis within the lung tissue. In addition, non-replicating (persister/dormant) TB assays are highly variable.

When compounds progress to animal models, costs escalate further due to the time scales involved and containment issues detailed above. The mouse model is used as an industry standard; however, mice fail to form granulomas that reproduce the tissue environment seen in humans.

Historical TB drugs also do not conform to the more standard assessment of a ‘drug like’ molecule. Recent analysis by Ekins et al has shown TB active drugs generally have higher LogPs, a higher number of Lipinski’s rule of five alerts, lower polar surface area, less hydrogen bond donors and a lower atom count when compared to other FDA-approved drugs.[9]

From a development perspective, this would infer that TB active compounds are more likely to fail as they progress through the development pipeline. However, knowledge of these trends can only help inform future development programs. These factors, combined with limited success in the development of an efficacious vaccine against TB, highlight the challenges ahead.

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Recent developments – light at the end of the tunnel?

Predictive models 

More recent research has set out to address some of the issues detailed above. Brodin et al have been instrumental in the development of improved in vitro assays. They have developed a high throughput phenotypic cell-based assay, involving fluorescent staining of intracellular acidic compartments in the macrophages, where Mtb resides. This is followed by automated confocal microscopy to quantitatively determine the intracellular localization of Mtb. This has been adapted into a drug screening tool and is used in conjunction with a standard replicating TB assay. Drugs selected through this process are more likely to reach the lungs and be able to penetrate the macrophages when put into an in vivo system.[10]

From an in vivo perspective, GlaxoSmithKline have played a key role in the development of shorter timescale in vivo representative models, although these are still within mice. Advances in positron emission tomography and computerized axial tomography allow images of the lungs of marmosets and rabbits to be monitored throughout drug treatment, and the TB disease progression or cure to be seen.[11]

Novel targets – TB respiratory chain 

Respiratory-chain inhibition-induced death represents a fundamental shift from traditional antitubercular drug design that have until recently relied on drugs that selectively target the replication machinery of Mtb. Antitubercular drugs developed to target the respiratory pathways should therefore have the potential to have sterilizing activity against current MDR- and XDR-Mtb strains. Targeting components of the Mtb respiratory chain has been shown by us, and other laboratories, to be effective in sterilizing both replicating and dormant Mtb.[12–17]

Recent approval of bedaquiline which targets the ATPase component of the respiratory chain (Figure 1), along with development of respiratory chain screening platforms[18] and investigations into the synergistic relationship of combining inhibitors of more than one respiratory chain component,[19] highlight the potential of these targets in future TB therapies.

Figure 1 – TB respiratory chain including ATPase, the target of bedaquiline
                                

TB Alliance 

TB Alliance has the largest portfolio of potential TB treatments in the world and is instrumental in translating the advances above into clinical regimens. Their ultimate vision is to develop a completely novel drug combination that can treat all forms of TB. The regimens they are currently evaluating in late-stage clinical trials reflect this goal – the more novel drugs in a regimen, the greater proportion of the population that it will be able to cover. Most recently, the Nix-TB study is among the first clinical trials to test a new regimen for XDR-TB. It is the first to test an all-oral drug regimen, comprised of drugs with minimal pre-existing resistance, which has the potential to shorten, simplify and improve treatment for XDR-TB.

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Future perspective

The future of TB drug development is multifactorial. In order to successfully feed the pipeline, continued development of more predictive models and screening technologies is vital to provide and progress a wealth of starting points and novel targets. The TB Alliance pipeline currently has 24 projects in the discovery phase. Continued industrial investment and TB Alliance support is essential to progress these projects to clinical development and beyond.

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References

  1. World Health Organisation Global Tuberculosis Report 2017 – Executive Summary, pp 1–3 (2017)
  2. Streicher EM, Müller B, Chihota V, et al. Emergence and treatment of multidrug resistant (MDR) and extensively drug-resistant (XDR) tuberculosis in South Africa. Infect Genet Evol. 12(4), 686–694 (2012)
  3. Koul A, Arnoult E, Lounis N, Guillemont J and Andries K. The challenge of new drug discovery for tuberculosis. Nature. 469(7331), 483–490 (2011)
  4. Goel D. Bedaquiline: A novel drug to combat multiple drug-resistant tuberculosis. J Pharmacol Pharmacother.  5(1), 76–78 (2014)
  5. Guillemont J, Meyer C, Poncelet A, Bourdrez X and Andries K. Diarylquinolines, synthesis pathways and quantitative structure–activity relationship studies leading to the discovery of TMC207. Future Med Chem. 3(11), 1345–1360 (2011)
  6. Xavier AS, Lakshmanan M. Delamanid: A new armor in combating drug-resistant tuberculosis. J Pharmacol Pharmacother.  5(3), 222–224 (2014)
  7. Matsumoto M, Hashizume H, Tomishige T, et al. OPC-67683, a nitro-dihydro-imidazooxazole derivative with promising action against tuberculosis in vitro and in mice. PLoS Med.  3(11), e466 (2006)
  8. Fox GJ, Menzies D. A review of the evidence for using bedaquiline (TMC207) to treat multi-drug resistant tuberculosis. Infect Dis Ther. 2, 123–144 (2013)
  9. Ekins S, Kaneko T, Lipinski CA, et al. Analysis and hit filtering of a very large library of compounds screened against Mycobacterium tuberculosis. Mol. BioSyst. 6, 2316–2324 (2010)
  10. Brodin P, Poquet Y, Levillain F, et al. High content phenotypic cell-based visual screen identifies Mycobacterium tuberculosis acyltrehalose-containing glycolipids involved in phagosome remodeling. PLoS Pathog. 6(9), e1001100 (2010)
  11. Via LE, Schimel D, Weiner DM, et al. Infection dynamics and response to chemotherapy in a rabbit model of tuberculosis using [18F]2-fluoro-deoxy-D-glucose positron emission tomography and computed tomography. Antimicrob Agents Chemother. 56(8), 4391–4402 (2012)
  12. Haagsma AC, Abdillahi-Ibrahim R, Wagner MJ, et al. Selectivity of TMC207 towards mycobacterial ATP synthase compared with that towards the eukaryotic homologue. Antimicrob Agents Chemother. 53(3), 1290–1292 (2009)
  13. Kana BD, Machowski EE, Schechter N, Shin JT, Rubin H and Mizrahi V. Electron transport and respiration, pp 35–64 in Mycobacterium: Genomics and Molecular Biology, Parish T, Brown A, (eds.) Horizon Press, London (2009)
  14. Koul A, Dendouga N, Vergauwen K, et al. Diarylquinolines target subunit c of mycobacterial ATP synthase. Nat Chem Biol.  3(6), 323–324 (2007)
  15. Rao SPS, Alonso S, Rand L, Dick T and Pethe K. The protonmotive force is required for maintaining ATP homeostasis and viability of hypoxic, nonreplicating Mycobacterium tuberculosis. Proc Natl Acad Sci USA. 105(33), 11945–11950 (2008)
  16. Weinstein EA, Yano T, Li LS, et al. Inhibitors of type II NADH:menaquinone oxidoreductase represent a class of antitubercular drugs. Proc Natl Acad Sci USA. 102(12), 4548–4553 (2005)
  17. Hong WD, Gibbons PD, Leung SC, et al. Rational design, synthesis, and biological evaluation of heterocyclic quinolones targeting the respiratory chain of Mycobacterium tuberculosis. J Med Chem. 60(9), 3703–3726 (2017)
  18. Bald D and Koul A. Respiratory ATP synthesis: the new generation of mycobacterial drug targets? FEMS Microbiol Lett.  308(1), 1–7 (2010)
  19. Biagini GA, Ward SA, Nixon GL and O'Neill PM. Combination Product, WO2017103615A1 (2017)
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