From lab to launch….

Drug discovery is a time consuming and expensive undertaking. Currently it commonly takes between 10 to 15 years to get from the start of the discovery process through to launch (if you make it !) and the cost can range from $2 billion to $5 billion depending upon whose statistics you reference. The preclinical discovery phase tends to be short and relatively cost effective, the output of which then runs the gauntlet of a battery of toxicity and safety tests before being allowed to enter testing in humans. After what is usually a relatively short efficacy study in a small number of patients provides a suggestion that the drug may work, a series of larger and longer clinical studies ensure that the drug is both safe and effective. If all goes well in these studies the regulatory authorities, usually FDA or the EMEA, will review the extensive data package and if opinion is positive, give approval for the drug to be launched for use in routine clinical practice.

We all want this process to be faster and more effective but without any compromise on safety and determination of efficacy – and by ‘we’ I mean drug discovers, patients, the pharmaceutical industry and regulators. We also want the process ideally to be more efficient and predictive with less chance of failure, particularly in late stage, expensive studies (one of the major reasons the costs above are in the billions – if every drug that entered clinical studies worked the cost of discovering a new drug would be ~$350 million). A focus on orphan diseases where patients are more homogeneous and we have strong understanding of the genetic basis of their disease is delivering higher success rates. Perhaps the poster child for this approach has been cystic fibrosis and the introduction of therapies that effectively address the genetic defect by repairing the defective protein – in CF it’s the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride ion channel. Vertex Pharmaceuticals introduced the first of its expanding portfolio of CFTR repair therapies in 2012 – this was the CFTR potentiator, ivacaftor (tradename Kalydeco). Ivacaftor demonstrated impressive clinical effects in patients with a specific CFTR mutation (G551D) and has demonstrated efficacy in a number of follow on trials in CF patients with mutations which are biophysically similar to G551D (a CFTR protein that makes it to the cell membrane but is loathe to open). G551D is the third most common CF disease causing mutation that accounts for somewhere between 2 – 5% of the CF population so relatively rare as there are estimated to be ~70,000 patients worldwide.

So what happens if you have a medicine which you believe will deliver benefit to additional patients but they are few and far between, with not enough to undertake a robust phase 3 trial ? This was the conundrum facing Vertex when looking to expand the labelling for Ivacaftor. In what is the first of its kind the FDA granted expanded approval to Vertex for Ivacaftor based upon in vitro data only. This could be a landmark step and the FDA has acknowledged that this approach could have implication for other drugs that have a well understood safety profile and address well characterised diseases. With Ivacaftor Vertex have a drug with a robust safety package, a strong understanding of its mechanism of action and have put considerable effort into assessing the correlation between preclinical cellular assays, clinical biomarkers and registerable endpoints. To support the request for expanded labelling Vertex expressed ~50 mutations in Fisher rat thyroid cells, a cell system widely used by the CF field as it has low expression of background chloride channels and can be used in a variety of assays (including Ussing chamber ion transport). Mutations that delivered a 10% increase in chloride transport when treated with Ivacaftor were considered responsive. This wasn’t an arbitrarily selected figure but one borne out by Vertex’s clinical experience with Ivacaftor and other compounds from their developing CFTR repair portfolio. Of those tested 23 mutations have been added to Ivacaftors labelling (26 failed to meet the criteria).

In real terms this means that ~900 CF patients in the US alone will now have the opportunity to access this breakthrough medicine – my congratulations to Vertex for pioneering the approach and my congratulations to the FDA for entertaining it….let’s hope it can be pursued for many other diseases.

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Image source:

Blog written by Martin Gosling


Durmowicz A.G et al (2018) The FDA’s experience with Icavaftor in cystic fibrosis: establishing efficacy using in vitro data in lieu of a clinical trial. Ann Am Thorac Soc. 2018 Jan;15(1):1-2. doi: 10.1513/AnnalsATS.201708-668PS.

Kingwell K (2017) FDA Oks first in vitro route to expanded approval. Nature Reviews Drug Discovery; doi:10.1038/nrd.2017.140


AI – a cure for the ROI?

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The face of the Pharmaceutical industry has changed beyond recognition over the past 20 years with many of the major players passing through multiple rounds of M&A, calving off large swathes of their portfolios, synergising, repurposing drugs ………all ultimately to improve Return On Investment (ROI). It is no secret the sector has had a rough ride with blockbuster drugs becoming increasingly rare, only ≈10% of drug candidates in phase I reaching approval in the years 2006-2015 (1) , increased payer pressure to cut prices, company revenues taking a hit as patent cliffs pass by and a dearth of innovative medicines being brought to the market.

How long will companies be able to sustain the significant cost of R&D whilst still turning enough of a profit to satisfy shareholders? The morality of industrial drug discovery (DD), long questioned in any case by those outside the industry, will be under serious scrutiny – not hard to see why with companies like Gilead charging upwards of $80,000 for a full course of the hepatitis C drug Sovaldi (2).  Take Ebola for instance.  Prior to the 2014 outbreak in West Africa (3) Ebola may have been viewed as an African problem and perhaps not an attractive area for investment.  After the outbreak and associated hysteria in certain corners of Western society all of a sudden this had the potential to be a little more than just an African problem.  Ebola was discovered in 1976 yet a study by the University of Edinburgh in 2015 estimated around half of all funding for Ebola research occurred in the 2014-2015 period after the outbreak.

Even the philanthropy of the Wellcome Trust is driven by ROI which unlike VC funding, is perhaps based more on intellectual than financial value, but here too we see a move away from traditional DD as demonstrated by the demise of the Seeding Drug Discovery Initiative. Granted this change in focus may be designed to generate new targets or technologies but the sentiment is clear; as traditional DD becomes more difficult with target patient populations potentially dwindling as a result of increased personalised/specialised therapies or peripheral areas of unmet need, where is the motivation for investment?

We are in desperate need of new anti-bacterials, as the population becomes older the prevalence of dementia is on the rise and alongside the ever present spectre of cancer all represent substantial investment if we are to have a meaningful impact in the development of effective treatments for these indications. It is clear that with the patient heterogeneity and the variable aetiology of these conditions that the model of drug discovery to date needs a significant change in prosecution.  In an effort to speed up the DD process we have seen a recent spate of AI-Large pharma collaborations (4/5/6) but are these tools merely ways to speed up old methods or will they genuinely result in the generating novel targets which might otherwise remain undiscovered by conventional means of investigation?

Regression analysis such as QSAR has long been used within DD to correlate physiochemical and functional parameters to guide chemical synthesis programs. Correlations between various ‘attributes’ (derived from principal component analysis) are used to generate a model which can be used to predict the behaviour of new compounds.  Of course the model is only as good as the number of data points and parameters used to define it and, once defined, remains unchanged.  The essential difference is that AI (specifically Deep learning) generates self-adapting models using a multi layered network approach that wasn’t really possible before the development of GPUs which allowed the parallel processing of vast amounts of data.  The data is assessed according to any one of its ‘attributes’ in the ‘top layer’ before being passed to the ‘second’ layer and processed according to another attribute etc. and as this is an unguided approach the systems needs a sufficient volume of data and many iterations to generate a reliable model of correlation.  After each iteration the algorithms used to generate the correlations can then be altered as the network ‘learns’ from the previous iteration.  Like any other computer model generating system though, it is liable to the ‘garbage in, garbage out’ (GIGO) concept.

It is easy to see how AI can be and is effective in, for instance, developing candidate compound libraries generated from well-characterised protein and protein/ligand crystal structures and suggest routes of synthesis (7) but the question of how AI can truly revolutionise an ailing industry is a long way off being answered. The regression analysis used in AI is the same as that used in QSAR for years, essentially it’s just the volume of data and the learning aspects that are different.  The hope, however, is that AI will generate unique correlations that have thus far eluded us or only revealed themselves serendipitously.  Pfizer’s hopes to quickly analyse and test hypotheses from “massive volumes of disparate data sources” (including more than 30 million sources of laboratory and data reports as well as medical literature)(8) seems, to the untrained eye (mine!) to be fraught with danger regarding curation of the input data.  Even in the simplest instance of a standard compound IC50, how would un-curated inter-institution variations affect a blind, self-determining analysis?  Perhaps, conversely to the GIGO scenario, considering the volume and disparate nature of data used (literature, experimental, predicted) and correct application of principal component analysis in a given enquiry, AI may actually be resilient to these small variations.

With regard to mental health we only have to look at our efforts to provide an objective definition of a subjective experience in the reconceptualization/re-categorisation/inclusion/elimination of mental disorders in subsequent editions of the ‘Diagnostic and Statistical Manual of Mental Disorders’ (9) to know that our understanding of these disorders is in a constant state of refinement.  AI assessment of a potentially novel pathway/target based on the prevailing definitions of a given condition superposed on the inherently variable subjective clinical data would, it seems, yield different answers from one year to the next.

AI has been hampered not necessarily by the development of algorithms but by the availability of sufficiently broad, curated training data sets and the development of both GPUs and adequate storage (10). With the advent of ‘-omics’ technologies able to acquire vast amounts of data, only relatively recently have the means been developed by which we can effectively interrogate this huge repository of information.  It would seem then that a standardised curation of this data is of primary importance if the industry is going to rely heavily on AI to effectively generate new medicines……notwithstanding the importance of generating clinically verified biomarkers in parallel…..but that’s for another blog!!

We only have to look at GenBank as an example. From its inception in 1982 it took until 2003 for the first release of the curated RefSeq collection.  I remember trying to identify novel splice variants in the late 90’s only to be frustrated by poorly annotated and simply incorrect sequences.  Contemporary parallels can be drawn with the Protein Data Bank (PDB) especially in relation to a) the Structural genomics program where un-curated, non-peer reviewed, homology based structures are being submitted to the database (11), and b) inaccurate Protein-Ligand co-crystal structures (12).

It is clear that AI can/will be/is a benefit during every step of drug discovery and that algorithm refinement is an ongoing, iterative process but what is not currently clear is whether AI will deliver where, for instance, HTS failed in dramatically impacting on the inefficiencies of the DD process (13). I have no doubt that very soon AI will become a fundamental part of all aspects of health care and drug discovery but I wonder whether this will actually precede the demise in scale of small molecule drug design and highlight the need to pursue other avenues (e.g. Gene therapy/Biologics) more vigorously.   In any case as the complexity of both the diseases/unmet need and the required solutions increase it will be interesting to see how ROI will be maintained and how much more Big Pharma consolidation we will see over the coming years.

Blog written by Marcus Hanley


  3. Fitchett et al. (2016) Ebola research funding: a systematic analysis 1997–2015, Journal of Global Health. Available from:
  9. The DSM-5: Classification and criteria changes. World Psychiatry. 2013 Jun; 12(2): 92–98. Published online 2013 Jun 4.
  11. Domagalski et al. (2014) The Quality and Validation of Structures from Structural Genomics MinorMethods Mol Biol. 2014 ; 1091: 297–314
  12. Reynolds, Charles H (2014) Protein-ligand cocrystal structures: we can do better. ACS medicinal chemistry letters, 10 July 2014, Vol.5(7), pp.727-9





Using Biochemical Light-switches to Illuminate Ion Channel Activity

There’s no doubting that optogenetics is an important recent development within the field of neuroscience. Channelrhodopsins, non-mammalian proteins that conduct ions in response to specific wavelengths of light, have now been inserted into various neuronal pathways to demonstrate the use of light to control modalities as diverse as vision, hearing, pain and motor control. In November 2017, The Scientist reported on progress in human clinical trials using channelrhodopsins in combination with viral vectors to restore a degree of function in damaged sensory neurons in response to light1. In a study conducted by Allergan, patients suffering from retinitis pigmentosa were injected with virus carrying the genetic signal to express channelrhodopsins specifically in retinal ganglion cells, bypassing the damaged light-detecting cells of the retina, enabling a rudimentary sense of light-detection in patients that were previously totally blind. Although primarily a safety study, it has shown promising progress in the field which may soon see developments towards treating hearing loss and chronic pain using a similar approach.

However, alongside the use of non-mammalian light-activated proteins to control neuronal activity, an alternative light-based approach has been developing which has direct and immediate usefulness as a tool in the field of drug discovery. The use of light to reversibly deliver ligand to a native protein receptor or ion channel, or ‘optopharmacology’, is the subject of an interesting recent mini-review by Bregestovski, Maleeva and Gorostiza2. For drug discovery, the use of these chemical photo-switches enables the rapid, and most importantly, reversible activation of ion channel function in response to light. Ligand-gated channels are the subject of this particular review, but much work with voltage-gated channels and G-protein-coupled receptors has now also been published. This approach provides a huge step forward from the previous use of caged-compounds in flash photolysis – often used, for example, to study synaptic transmission, but would leave the preparation awash with ligand that was slow to clear by re-uptake/diffusion, meaning difficult and slow ‘one-hit’ experimentation.

At the Ion Channel Modulation Symposium in Cambridge last year (2016), Dirk Trauner spoke about the development of these tools and demonstrated their use in research conducted both within his group and in conjunction with collaborators around the world, showing examples (see figures 1 & 2 below) of the use of photochromic ligands in both their soluble (PCL) and tethered (PTL) forms.

These two forms are defined by the nature of their interaction with target proteins – PCLs are designed to mimic the ligand of a specific receptor but are freely diffusible and may not exhibit sub-type specificity within a tissue. PTLs, as their named suggests, become covalently tethered to their target, usually via naturally-occurring or genetically modified cysteine residues, conferring a much higher degree of selectivity. On exposure to specific wavelengths of light, the molecules photoisomerize between cis-and trans- states, enabling ligand-receptor interaction that triggers either activation or deactivation of the target protein.

Of the two types, PCLs are the simplest to use. Figure 1 shows the impressive degree of temporal control of gained over the function of the capsaicin receptor TRPV1 in the presence of 1uM of a ‘photolipid’ PCL (here, an azobenzene combining the vanilloid head-group of capsaicin with photoswitch-containing fatty-acid chain (AZCA derivatives)) in response to simply varying light stimulation between 350 and 450 nm.

Figure 1: reproduced from Frank et al (2015)3

Sarah 1

Having proved the principle in TRPV1-expressing HEK cells, optical switching in the presence of this PCL was applied to isolated mouse DRG neurones, and c-fibre nociceptive neurones in saphenous nerve preparations, both of which contain native TRPV1 receptors. All showed rapidly reversible non-selective cation conductance in response to the shorter wavelengths of light, translating into nerve depolarisation and action potential firing in native neurones – responses which were absent in TRPV1-/- knockout mice.

Trauner also presented work using PTLs, and show-cased developments made in collaboration with US colleagues to extend the chemical tether to reinforce its chemical stability and reduce the chance of off-target attachment. Their new ‘PORTL’ (photoswitchable orthogonal remotely tethered ligand), shown in figure 2a, was used to demonstrate dual optical control of mGluR2 and GluK2 expressed in the same cell, differentially responding to the specified wavelengths of light (figure 2b).

Figure 2: reproduced from Broichhagen et al (2015)4                 Sarah 2

This elegant chemistry is a powerful tool for studying ion channel-mediated physiology. Its use, for example, to selectively activate or silence particular neurones, or sub-populations of heteromeric channels containing a common tagged subunit, with a degree of spacial and temporal control unachievable with perfusion, enables more qualitative assessment of the interaction between  new possible therapeutic compounds and their target proteins. And like channelrhodopsins, the use of these photochromic ligands as therapies in their own right is also possible and currently being investigated.

Blog by: Sarah Lilley


1 The Scientist Nov 16 2017 article by Shawna Williams

2Bregestovski, P., Maleeva, G., and Gorostiza, P. (2017) Light-induced regulation of ligand-gated channel activity. British J Pharm, doi: 10.1111/bph.14022.

3Frank, JA., Moroni, M., Moshourab, R., Sumser, M., Lewin, GR., and Trauner, D. (2015) Photoswitchable fatty acids enable optical control of TRPV1. Nature Comms 6, doi:10.1038/ncomms8118

 4Broichhagen, J., Damijonaitis, A., Levitz, J., Sokol, KR., Leippe, P., Konrad, D., Isacoff, EY., and Trauner, D. (2015) Orthogonal optical control of a G protein-coupled receptor with a SNAP-tethered photochromic ligand. ACS Cent Sci 1 383-393, doi: 10.1021/acscentsci.5b00260

The Silicon switch in Drug Discovery

Hit-to-Lead optimisation is a crucial step in Drug Discovery. It implies the wise modification of hit molecules by following specific pharmacologic and pharmacokinetic parameters. Many strategies can be employed to tackle this challenge, one of them is bioisosterism. Bioisosters are moieties or atoms that show the same physicochemical properties and biological activity. Thus, medicinal chemists can rely on a large chemical toolbox, for example, by changing an amide bond to an oxazole or shielding a carboxylic acid with a tetrazole. This all depends how we want to drive the series (in terms of physicochemical properties) through the bottleneck of the Drug Development. Bioisosterism is also widely used for the IP space expansion of chemical libraries.

In this light, I would like to discuss the “big brother” of carbon, the silicon. Within the third row of the periodic table, silicon is located below the carbon; they share the same valency of 4 and commonly forms tetrahedral molecules, the most common silicon linkage being Si-C and Si-O. The replacement of carbon by silicon within bioactive compounds could therefore yield new compounds with different properties for lead optimization.1 Small chemical differences exist between silicon and carbon. Indeed, it is known that the C-Si bond is 20% larger than the C-C bond – this observation has consequences on the shape and conformation of the molecule, which in turn leads to different interactions with the biological system. Silicon compounds are also more lipophilic than their carbon congeners. Therefore, switching from carbon to silicon could improve cell penetration, which is very important for compounds targeting the central nervous system for example. Nevertheless it also creates solubility and metabolic clearance issues that could be mitigated, depending where we want to put the cursor in terms of DMPK. A “hidden” feature of silicon is that it can form hexacoordinated compounds in comparison with carbon: that has great significance in Medicinal Chemistry since many potent transition state mimics containing silanediols have been developed. Finally, silicon is more electropositive than carbon, which leads to a difference in bond polarity and ultimately to a different biological outcome, one good example is the ammonium/silicon exchange found in Zifrosilone (acetylcholinesterase inhibitor).

A lot of work have been produced recently towards the pharmacological evaluation of new silicon-containing molecules (Figure 1), however none of these progresses has yet yielded a marketed drug. As said recently by the blogger Derek Low,2 silicon stays in the shadows, despite the huge potential offered by this element in balancing physicochemical properties with DMPK and lowering compound attrition during the lead optimization phase.

I believe that a new era for silicon in Drug Discovery will come soon; we cannot neglect this element any longer.

Mo 1

Figure 1. Examples of some bioactive silicon-containing molecules with enhanced pharmacology and DMPK

Blog written by Mohamed Benchekroun


(1)          Ramesh, R.; Reddy, D. S. Quest for Novel Chemical Entities through Incorporation of Silicon in Drug Scaffolds. J. Med. Chem. 2017.

(2)          Lowe, D. Silicon Stays in the Shadows (accessed Dec 7, 2017).

Mutational Signatures in Cancer

A cancer carries thousands of somatic mutations, most of which provide no selective advantage to clones which acquire them. Much research is focussed on the few driver mutations that do confer such an advantage; how such mutations enable cancer development and whether they can be targeted as cancer therapies.  However, the recent reduction in cost of large scale sequencing (either whole exome or whole genome sequencing), has allowed mutational information to be used in a different way.  The study of mutational signatures can provide information about the mutagens to which a patient has been exposed to over a lifetime, any DNA repair mechanisms malfunctioning within the tumour, and potential therapeutic agents to which the tumour may be sensitive (Helleday, Eshtad et al. 2014).

Following large scale sequencing, signatures are generated by categorising base pair substitutions into 6 categories (C.G→A.T, C.G→G.C, C.G→T.A, T.A→A.T, T.A→C.G, T.A→G.C) and also taking into account the bases on each side of the substituted base. This gives 96 possibilities and each of these can be scored, giving an image such as that below.  This is a signature common in colorectal cancers, and is a product of defects in the mismatch repair (MMR) pathway.

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Figure 1. An example of a mutational signature from a MMR defective tumour. Taken from

Sequencing can also provide information about other types of mutation.  Indels, which are insertions or deletions can be quantified, together with their average size.  This provides further information about the damage/repair environment within the tumour.  For example, indels between 4 and approximately 50 bases, surrounded by mircohomology can be indicative of tumours relying on non-homologous end joining due to a defect in homologous recombination (HR).  Information about gross chromosomal rearrangements, such as tandem duplications, translocations and karyotypic variations can be integrated with base substitution information.  This can be viewed in a circos plot.  Below are examples of these plots from a tumour defective in homologous recombination (A) with large numbers of rearrangements and another defective in MMR (B) with large numbers of substitutions.

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Figure 2. Circos plots of tumours with different repair defects.  A is HR defective and B is MMR defective.  Adapted from (Davies, Morganella et al. 2017).

So what is the value of studying these mutational signatures? Since they give a historical perspective on the damage accrued by the genome, they can be used to monitor historical exposure to various agents.  For example, the presence of a particular mutational signature associated with exposure to Aristolochic acids (present in traditional medicines) has been identified to be present in a large number hepatocellular carcinomas in Asia (Ng, Poon et al. 2017). This in turn can inform policy on the availability of such agents.

Additionally study of mutational signatures allows the improved targeting of therapies. HR defective tumours present a distinct mutational signature and such tumours are generally sensitive to PARP inhibitors. MMR defective tumours carry a high mutational load and respond well to immune checkpoint inhibitors such as anti-PD-1 antibodies (Le, Durham et al. 2017). Although colorectal tumours are routinely examined for MMR status to allow specific treatment, MMR defective tumours in other cancer types are likely missed. A recent study showed that a small percentage of breast cancers carry MMR defects without germline mutation in MMR genes (Davies, Morganella et al. 2017). These tumours may respond well to immune checkpoint blockade. Therefore, the classification of tumours by mutational signatures could provide a broader but more highly targeted use for several existing therapies. Although currently these are only identified in a research setting, the falling cost of sequencing may allow such characterisation to be part of the process in treatment of cancer patients.

Blog written by Jess Hudson


Davies, H., S. Morganella, C. A. Purdie, S. J. Jang, E. Borgen, H. Russnes, D. Glodzik, X. Zou, A. Viari, A. L. Richardson, A. L. Borresen-Dale, A. Thompson, J. E. Eyfjord, G. Kong, M. R. Stratton and S. Nik-Zainal (2017). “Whole-Genome Sequencing Reveals Breast Cancers with Mismatch Repair Deficiency.” Cancer Res 77(18): 4755-4762.

Helleday, T., S. Eshtad and S. Nik-Zainal (2014). “Mechanisms underlying mutational signatures in human cancers.” Nat Rev Genet 15(9): 585-598.

Le, D. T., J. N. Durham, K. N. Smith, H. Wang, B. R. Bartlett, L. K. Aulakh, S. Lu, H. Kemberling, C. Wilt, B. S. Luber, F. Wong, N. S. Azad, A. A. Rucki, D. Laheru, R. Donehower, A. Zaheer, G. A. Fisher, T. S. Crocenzi, J. J. Lee, T. F. Greten, A. G. Duffy, K. K. Ciombor, A. D. Eyring, B. H. Lam, A. Joe, S. P. Kang, M. Holdhoff, L. Danilova, L. Cope, C. Meyer, S. Zhou, R. M. Goldberg, D. K. Armstrong, K. M. Bever, A. N. Fader, J. Taube, F. Housseau, D. Spetzler, N. Xiao, D. M. Pardoll, N. Papadopoulos, K. W. Kinzler, J. R. Eshleman, B. Vogelstein, R. A. Anders and L. A. Diaz, Jr. (2017). “Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.” Science 357(6349): 409-413.

Ng, A. W. T., S. L. Poon, M. N. Huang, J. Q. Lim, A. Boot, W. Yu, Y. Suzuki, S. Thangaraju, C. C. Y. Ng, P. Tan, S. T. Pang, H. Y. Huang, M. C. Yu, P. H. Lee, S. Y. Hsieh, A. Y. Chang, B. T. Teh and S. G. Rozen (2017). “Aristolochic acids and their derivatives are widely implicated in liver cancers in Taiwan and throughout Asia.” Sci Transl Med 9(412).


TMEM16A: Closing the circle

Raimund Dutzler and his lab have been the first group to solve the crystal structure of the mammalian mouse TMEM16A ion channel using cryo-electron microscopy (Paulino et al., 2017). This study is the first essential step to resolving the controversies which has raged in the ion channel community since the discovery of this protein responsible for the calcium activated chloride channel back in 2008 by 3 independent groups (Caputo et al; Schroeder et al; Yang et al., 2008). More recently Brunner et al. (2014) was the first to solve the crystal structure for the related fungal protein Nectria haematococca TMEM16 (nhTMEM16), a lipid scramblase.  Their hypothesis being that the TMEM16 protein family, consisting of ten genes (TMEM16A-k, missing out I) split from a common ancestral lipid scramblase and evolved in mammals to produce the only 2 known chloride ion channels, TMEM16A and TMEM16B, in the TMEM16 family. Up until this point functional studies had shown Ca2+ activation, voltage dependency and through mutagenesis which amino acids had an impact on chloride conductance in TMEM16A. Brunner et al’s X-ray structure, to a 2.6 Å resolution, gave rise to a number of profound questions about the chloride ion channels TMEM16A & B.

Their structure of the TMEM16 homodimer did not conform to ion channel dogma. Based on the homology model of the lipid scramblase X-ray structure for nhTMEM16A, Whitlock and Hartzel (2016) proposed that the calcium activated chloride ion conductance protein TMEM16A shared structural similarities to the lipid scramblases i.e. it was also an homodimer and each dimer had a subunit cavity or pore, but the chloride permeation channel was made up of half lipid, half protein and the Ca2+ binding site was located within the transmembrane domain of the subunit cavity of the protein. In June 2017 (TMEM16A: 2pores, or not 2 pores) I discussed 2 studies (Lim et al. 2016 & Jeng et al. 2016) using covalently linked mouse TMEM16A subunits with one of the two subunits carrying mutations, which confirmed that the TMEM16A homodimer had 2 independent chloride pores.

Raimund Dutzler’s lab are the first to report the structure of mammalian TMEM16A ion channel with cryo-electron microscopy of mouse TMEM16A at a resolution of 6.6Å (Paulino et al., 2017). They are proposing that the putative pore region of mTMEM16A is now an enclosed aqueous proteinaceous pore with a large intracellular vestibule that narrows to a chloride conducting pathway surrounded by alpha –helices (Figure 1). They show this is brought about by a realignment of helices, when compared to the nhTMEM16A X-ray structure, helices 4 and 6 move from the edges of the subunit cavity, in to enclose the aqueous proteinaceous pore and closing it off to membrane lipids (Figure 1). However, a drawback of this study is the resolution of the cyro-electron microscopy technique, as crucially it does not give the locations of amino acids side chains or the pitch of helices within the protein. We will await the increased resolution of an X-ray protein structure to confirm these important initial findings. Also, the protein was purified in the presence of high levels of Ca2+ and therefore could represent a non-conducting form of mTMEM16A.

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Figure 1. Mechanistic relationships within TMEM16 family.

(A) Depiction of the mTMEM16A pore. The molecular surface of the pore region is shown as grey mesh. The boundaries of hydrophobic (black) and polar regions (grey) of the membrane are indicated by rectangular planes. The positions of positively charged residues affecting ion conduction are depicted as blue and bound Ca2+ ions as green spheres. Hypothetical Cl ions (radius 1.8 Å) placed along the pore are displayed as red spheres. (B) Schematic depiction of features distinguishing lipid scramblases (left) from ion channels (right) in the TMEM16 family. The view is from within the membrane (top panels) and from the outside (bottom panels). The helices constituting the membrane accessible polar cavity in scramblases have changed their location in channels to form a protein-enclosed conduit. A and B, Permeating ions and lipid headgroups are indicated in red. (Paulino et al. (2017) eLife;6: e26232).

They tested their hypothesis with functional studies, mutating basic amino acids for neutral Alanines in both the vestibule and within the pore region of the mTMEM16A to see what impact this had on chloride conductance. They found, as predicted, that altering the charge in the vestibule had little impact on chloride conductance whereas, altering the charge in the pore had a more pronounced effect.

The Brunner et al. (2014) X-ray structure and the homology models that arose from it, gave rise to the controversy in the literature, trying to reconcile ion channel dogma with the available TMEM16A functional data and the nhTMEM16 X-ray structure. Paulino et al. (2017) has with this essential first mTMEM16A structure, albeit with the cryo-electron microscopy technique at 6.6Å resolution which needs to be confirmed with the increased resolution of an X-ray structure, resolved our understanding of how chloride ions pass through TMEM16A. And in mTMEM16A anyway, we still await elucidation of the human structure, this has come with the realignment of helices 4 and 6 closing the circle of the subunit furrow to form an aqueous chloride conducting pore.

Blog written by Roy Fox


  1. Paulino et al. (2017) eLife; 6:e26232
  2. Caputo et al. (2008) Science 322:590–594.
  3. Schroeder (2008) Cell 134:1019–1029.
  4. Yang et al. (2008) Nature 455:1210–1215.
  5. Brunner et al. (2014) Nature 516:207–212.
  6. Whitlock JM and Hartzell HC (2016) Eur. J. Physiol. 468: 455-473.
  7.  Lim et al. (2016) J. Gen. Physiol. 148:5, 375-392.
  8.  Jeng et al. (2016) J. Gen. Physiol. 148:5, 393-404.

Rare Activating Mutations in the Calcium Sensing Receptor (CaSR), and Resultant Autosomal Dominant Hypocalcemia (ADH): Current and Future Pharmacological Intervention


Activating mutations of the G protein-coupled receptor, calcium-sensing receptor (CaSR), cause the rare and difficult to treat autosomal dominant hypocalcemia (ADH) and Bartter syndrome type 5 (BS5).

These mutations lower the set-point for extracellular Ca2+ sensing. This leads to increased parathyroid hormone (PTH) secretion. Normally, PTH stimulates Ca2+ reabsorption in the kidney and inhibits disposal, in addition to regulating skeletal Ca2+ release and uptake in bone. PTH effects are mediated via the type-1 PTH receptor (PTH1R) that couples to the small G protein Gs and activates cAMP signalling. PTH also stimulates the 1/-hydroxylation of vitamin D compounds in the kidney, and indirectly stimulates Ca2+ uptake in the gut. The effects of PTH and vitamin D in kidney, bone, and gut elevate serum Ca2+ levels and complete the classic regulatory feedback loop of the Ca2+ homeostasis. Patients with activating mutations have absent or reduced parathyroid hormone (PTH) owing to CaSR mediated hypocalcaemia and suppression of PTH secretion, and development of hypercalciuria. The mechanism of this regulation and the involvement of [Ca2+]]i , ERK1/2, or other signalling mechanisms is under investigation but is not completely understood. Nephrocalcinosis and nephrolithiasis, an increased risk of calcifications of the basal ganglia and cataract formation and osteoporosis are frequent findings 1.

Current Therapies

There are several established clinically effective therapeutic alternatives for the hypercalcemic disorders e.g. Familial Hypercalciuric Hypercalcaemia (FHH), as a result of inactivating mutations of the CaSR, however the hypocalcemic disorders are difficult to treat.

Vitamin D analogs and Ca2+ supplementation is standard treatment to raise serum Ca2+ levels in ADH patients. However, this inevitably aggravates the hypercalciuria which frequently limits attempts to normalize serum Ca2+. Several other treatments e.g. hydrochlorothiazide was found to temporarily reduce hypercalciuria, and replacement of PTH1–34 (teriparatide) was generally effective in reducing symptoms and/or raising serum Ca2+. Although urinary Ca2+ excretion declined or was constant despite rising serum Ca2+ levels in most patients, nephrocalcinosis can develop despite continuous PTH therapy. In ADH the kidney responds with increased Ca2+ excretion to an increased filtered Ca2+ load produced by any rise of serum Ca2+ levels. This most likely further elevates the risk of renal complications. The effects of CaSR predominate the effects of PTH on tubular reabsorption of Ca2+ in the kidney. For this reason, the activated CaSR in ADH and BS5 reduces the desired effects, and increases the adverse effects, of conventional therapeutic attempts 2.

At present then most patients remain symptomatic despite intensive therapy with all available strategies. At best, the available therapeutic options reduce symptoms without further increasing the elevated risk of tissue complications. Complete symptom relief and the reduction of long-term complications caused by the underlying disease itself are currently not achievable and none of the current therapeutic strategies corrects the underlying pathophysiology.

Future Pharmacological Intervention

There is a need to target the defect in CaSR to correct the underlying pathophysiology, and functional modulation of CaSR can be achieved by allosteric modulators. A positive allosteric CaSR modulator, the calcimimetic cinacalcet is presently used to treat FHH. Negative allosteric modulators or calcilytics directly inhibit CaSR and have been developed to stimulate endogenous PTH secretion, as an alternative to injections, to promote bone formation in osteoporosis. These drugs may be useful in reducing excessive CaSR activity in ADH and BS5 patients3.

Negative Allosteric Modulators in vitro and in rodents

To date only wild-type receptors or enzymes have been studied in vitro. To pharmacologically correct the molecular cause of ADH and BS5, the function of altered CaSR or G protein/11 (GNA11), will need to be rectified and the efficacy of calcilytics needs to be established. Over 70 activating CaSR and GNA11 mutations that cause ADH or BS5 have been described and functional in vitro tests with calcilytics have been reported for 32 activating CaSR and two activating GNA11 point mutants, and all were sensitive to at least one calcilytic in vitro. Four of these mutants (A840 V, Q245R, E228K, and E228A) were also sensitive in vivo4.

Studies to date have used amino-alcohol compounds Ronacaleret (SB-751689); NPSP795 (SB- 423562); SB-423557 (prodrug of NPSP795); MK-5442 (JTT-305) and finally the quinazolinone AXT914.

The in vivo effects of calcilytics have been studied in CaSR C129S and A843E knock-in mouse models. These models mimic the human ADH phenotype, with decreased serum Ca2+ and PTH, and increased serum phosphate levels. These mice also showed hypercalciuria and reduced urinary cAMP excretion. MK-5442 or NPS 2143 increased serum Ca2+ and PTH but stabilized or even decreased urinary Ca2+ excretion. MK-5442 also increased urinary cAMP excretion, and administration for 3 months reduced Ca2+ excretion and prevented renal calcification. By contrast, long-term subcutaneous PTH injections also increased serum Ca2+ but failed to reduce Ca2+ excretion and did not prevent renal calcification 4,5.

Negative Allosteric Modulators in Clinical Trial

In man, phase I and II clinical trials with calcilytics with a particularly short serum half-life have been developed to stimulate endogenous PTH secretion, as an oral alternative to PTH injections, to enhance bone formation in osteoporosis in postmenopausal women. Serum Ca2+ levels were normal at baseline in these participants and therefore they were presumed to have wild-type CaSR. Serum Ca2+, phosphate, and PTH levels were determined, as well as renal Ca2+ excretion 6.

All drugs were administered orally once daily, with the exception of NPSP795, which was given intravenously. These trials for were relatively unsuccessful for osteoporosis and no alteration in bone mineral density was appreciated. However, a dose-dependent increase in serum Ca2+ levels was consistently observed. Calcilytics are so far generally well tolerated with most common adverse effects being mild i.e. fatigue, headache, constipation, diarrhea, nausea, and dyspepsia.

These studies performed in wild-type CaSR patients provide valuable insight into the possible therapeutic use in ADH patients.

Calcilytics in ADH patients

A small Phase II trial with the calcilytic NPSP795 for the treatment of five ADH patients harbouring the A840 V, Q245R, E228K, and E228A mutations have been reported recently. Here, serum Ca2+ levels were maintained despite fasting and no Ca2+ or vitamin D supplementation with one participant developing hypercalcemia 7. No clinical trials have been performed in patients with BS5.

All calcilytic trials discussed reported a short-lived dose-dependent increases in PTH and Ca2+, followed by a return to baseline 6–12 h after administration. These results are in line with the rapid pharmacokinetic profiles of ronacaleret 6 and AXT914 (tmax 1–2 h, t½ 4–5 h) 8 and NPSP795 (t½ < 1h after i.v. administration, tmax 2-3h, t½ 1.4-3.7h after oral administration of the prodrug SB423557).

The results of these clinical trials are promising. Considering that different calcilytics from different chemical classes (amino-alcohol and quinazolinones) with different modes of action exert similar biochemical effects, implies that these effects are specific to calcilytics, and are not a single compound or chemical class effect, broadening the opportunity for calcilytic development. Taken together, there is still an unmet need for ADH patients and the repurposing of calcilytics for in this population is a promising approach for these difficult to treat diseases.

Blog written by Elizabeth Owen

  1. Mayr, B.M. et al. (2015) Genetics in endocrinology: gain and loss of function mutations of the calcium sensing receptor and associated proteins: current treatment concepts. Eur. J. Endocrinol. 174, R189–R208
  2. Mitchell, D.M. et al. (2012) Long-term follow-up of patients with hypoparathyroidism. J. Clin. Endocrinol. Metab. 97, 4507–4514
  3. Hu, J. and Spiegel, A.M. (2007) Structure and function of the human calcium-sensing receptor: insights from natural and engineered mutations and allosteric modulators. J. Cell. Mol. Med. 11, 908–922
  4. Dong, B. et al. (2015) Calcilytic ameliorates abnormalities of mutant calcium-sensing receptor (CaSR) knock-in mice mimicking autosomal dominant hypocalcemia (ADH). J. Bone Miner. Res. 30, 1980–1993
  5. Hannan, F.M. et al. (2015) The calcilytic agent NPS 2143 rectifies hypocalcemia in a mouse model with an activating calcium-sensing receptor (CaSR) mutation: relevance to autosomal dominant hypocalcemia type 1 (ADH1). Endocrinology 156, 3114–3121
  6. Caltabiano, S. et al. (2013) Characterization of the effect of chronic administration of a calcium-sensing receptor antagonist, ronacaleret, on renal calcium excretion and serum calcium in postmeno- pausal women. Bone 56, 154–162
  7. Ramnitz, M. et al. (2015) Treatment of autosomal dominant hypocalcemia with the calcilytic NPSP795. J. Bone Miner. Res. 30 (Suppl. 1), SA0002
  8. John, M.R. et al. (2014) AXT914 a novel, orally-active parathyroid hormone-releasing drug in two early studies of healthy volunteers and postmenopausal women. Bone 64C, 204–210



Breaking Convention with Sulfoximines – from Lab Oddity to Clinical Candidate

In 2013 a bold decision taken by Lücking et al[1] to incorporate a sulfoximine group into a lead series overcame all of the fundamental issues of the project and lead to the discovery of BAY 1000394 as a clinical CDK inhibitor (Fig 1) – who would have thought it?

The sulfoximine strategy was just one of the concepts that the team from Bayer explored to remove carbonic anhydrase (CA) activity whilst maintaining CDK activity. Fortuitously, the inclusion of the sulfoximine moiety (BAY 1000394) abolished CA activity completely and also improved many of the pharmacokinetic properties of the lead (Fig 1).

Scott 1

Fig 1: Initial HTS hit (1); para-sulfonamide (2); clinical pan-CDK inhibitors ZK304709 and BAY 10003941

Perhaps Lücking et al could have been forgiven for not pursuing sulfoximine approach – when reading this paper I’ve got to ask myself a) “would I have thought of that?”; b) “would I have gone to the trouble of making the sulfoximine and how would I have made it?”; c) “why would I make the sulfoximine?”; d) “are there any sulfoximines on the market today?”………..

  1. “Would I have thought of that?”

Short answer – No.

Long answer – I don’t think I had ever heard of a sulfoximine prior to reading this paper.  If somebody had drawn the structure on my fumehood perhaps I would have been sceptical about the functional group being drug-like.  Reading into the subject, it seems that sulfoximines were discovered recently (in terms of functional groups)[2] and that sulfoximine chemistry has been carried out by a handful of research groups, making it quite a niche area.  Traditional applications of sulfoximines have been centred on their use as chiral auxiliaries and ligands for asymmetric catalysis.2 So maybe it’s not too surprising that I would not have thought of that.

  1. “Would I have gone to the trouble of making the sulfoximine and how would I make it?”

OK, let’s assume I said yes to a).

Sulfoximines are not commercially available so ‘analogue bashing’ might be slow as this is unlikely to be a one-stepper! As sulfoximine chemistry has been (until recently) a niche area, synthetic methods have been limited and have various safety concerns.  One method that forms in-situ hydrazoic acid from the reaction of sodium azide, diphenyl sulfoxide and polyphosphoric acid has triggered an explosion in the past.[3]  If this was the only method then maybe I would not have bothered to make the sulfoximine.

Luckily over the last decade new and safer synthetic strategies have been established and are outlined in a recent paper by Tota et al who also report the first direct synthesis of NH-sulfoximines from sulfides[4] (Fig 2).  Work like this has helped to make sulfoximines more synthetically tractable.

Scott 2

Fig 2. Strategies and conditions for preparation of sulfoximines from sulfides4

  1. “Why would I make the sulfoximine analogue?”

Fortunately, Lücking has composed a mini-review on sulfoximines[5] and summarises nicely the chemical properties and versatility of the sulfoximine functional group (Fig 3).  The sulfoximine group is asymmetric at sulfur, stable, small, hydrophilic and offers another point of diversification at the nitrogen when compared to the sulfone analogue.5 BAY 1000394 exemplifies why the sulfoximine anlalogue should be made in cases where the sulfonamide analogue is active but requires further iteration to improve PK properties and off-target profile.

Scott 4

Fig 3. Sulfoximines and their chemical versitility5

  1. “Are there any sulfoximine drugs on the market today?

Short answer: No. However, in 2013 the EPA approved the first commercially available insecticide containing the sulfoximine moeity, Sulfoxaflor, to Dow Chemical Corporation.5

Scott 5

Fig 4. Dow Chemical Corporation’s Sulfoxaflor5

Long answer: Although there are no sulfoximine drugs on the market at the moment, at least three have reached the clinic.  All are kinase inhibitors for the treatment of cancer (Fig 5).5 BAY1143572 (Atuveciclib) is the first highly selective inhibitor of CDK9 to reach the clinic.  Guess what – it is another recent contribution by Lücking and co.[6]

Scott 6

Fig 5. Clinical sulfoximinesfor the treatment of cancer5

Recently, Sirvent and Lücking have incorporated the sulfoximine group into a range of marketed drugs with promising results in terms of improving PK properties whilst maintaining activity.2 Studies such as those outlined above are helping to raise the profile of sulfoximine chemistry, further developments in synthetic methodology and an increase in commercial sulfoximine building blocks would accelerate the likelihood of seeing the sulfoximine group in a drug molecule.2 Watch this space.

Blog written by Scott Henderson

[1] U. Lücking et al.  ChemMedChem 2013, 8, 1067

[2] J.A Sirvent and U. Lücking;  ChemMedChem 2017, 12, 487

[3] G. Satzinger, P. Stoss, Arzneim.-Forsch. 1970, 20, 1214

[4] A. Tota et al. Chem. Commun., 2017, 53, 348

[5] U. Lücking. Angew. Chem. Int. Ed. 2013, 52, 9399

[6] U. Lücking et al.  ChemMedChem 2017, 12, 1776.


Silent but deadly: Understanding the importance of ‘silent’ mutations in the Cystic Fibrosis gene

Cystic fibrosis results from the mutation of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene1. This mutation causes decreased chloride ion transport across the surface epithelia and dehydration of the airway surface liquid leading to the accumulation of thick viscous mucus which can trap pathogens setting up chronic bacterial infections.

More than 2,000 mutations in the CFTR gene have been identified1 – approximately 1,700 of which cause cystic fibrosis. An individual will inherit CF if both parents carry a mutation in the CFTR gene. These two faults may be the same or they could consist of two different mutations. The severity of disease varies between individuals and is partly due to how the inherited mutations affect the manufacture of the CFTR protein and how well it works within the cell.

The remaining 270 mutations identified include synonymous single nucleotide polymorphisms (sSNPs) or ‘silent’ mutations2. Due to the degenerative nature of the genetic code – i.e. more than one codon specifies each amino acid, sSNPs were considered to have no effect on the folding and therefore function of the protein produced. It should be noted that sSNPs do not cause disease by themselves, but are more common in patients with the most severe disease. Genome-wide association studies have linked sSNPs with over 50 human diseases so how can such ‘silent’ mutations be having such a detrimental effect?

This question was addressed by several teams, one led by Professor Igatova from the University of Hamburg and Professor Sheppard at the University of Bristol with help from colleagues in the Netherlands and the USA3.

The group at the University of Hamburg identified an sSNP, T2562G, which modifies the local translation speed of the CFTR, leading to detrimental alterations in the protein folding and function3. T2562G is one of the most common SNPs in the CFTR gene, with a prevalence of 34% in the general population4. This sSNP does not cause CF by itself but is it commonly found in patients with CFTR-related disorders5.

Professor Sheppard’s group at the University of Bristol showed that this inaccurate folding caused a narrowing in the final CFTR chloride ion channel which slowed the movement of the ions through the cell membrane3.

T2562G was found to introduce a codon pairing to a low-abundance tRNA which is rare in human bronchial epithelia but interestingly, not in other human tissues. The low abundance of the tRNA coded for by T2562G resulted in a far slower translocation speed at the Thr854 codon leading to vital changes in CFTR stability and function (Fig. 1B). The folding and function of T2562G-CFTR could be rescued by increasing the cellular concentration of the tRNA cognate to the mutant ACG codon (Fig. 1C).

This work illustrates how the function of the CFTR can be influenced by mutations in the CFTR gene that are not in themselves CF-causing. When these ‘silent’ mutations occur in conjunction with CF-causing mutations they can greatly alter the severity of disease. Understanding the effects of these silent changes on protein folding and function will help to understand the root cause of disease and perhaps ultimately find new treatments.

HollyFig. 1

The synonymous single nucleotide polymorphism (sSNP) T2562G inverts local translation speed in CFTR mRNA, which can be rescued by tRNAThr(CGU).

(A) Thr-854–encoding codon ACT in wild-type CFTR is translated fast, as its cognate tRNAThr(AGU) is relatively abundant. (B) T2562G sSNP converts the ACT triplet to ACG codon, which is read by the rare cognate tRNAThr(CGU) and reduces local ribosomal speed. Stochasticity in the delivery of tRNAThr(CGU) cognate to the ACG codon creates variations in the intimate translation speed of each ACG codon at this position and hence generates 2 distinct CFTR channel populations, one with wild-type–like (wtl) CFTR properties and a second with a reduced conductance and a more compact structure (small-conductance [sc] population). (C) Increase of the cellular level of tRNAThr(CGU) pairing to the mutated ACG codon restores ribosome speed at the rare Thr-ACG codon and rescues the CFTR conductance defect.

Blog written by Holly Charlton


  1. Cutting GR. Cystic fibrosis genetics: from molecular understanding to clinical application. Nat Rev Genet. 2015;16: 45–56.
  2. Veit G, Avramescu RG, Chiang AN, Houck SA, Cai Z, Peters KW, et al. From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations. Mol Biol Cell. 2016;27: 424–33.
  3.  Kirchner S, Cai Z, Rauscher R, Kastelic N, Anding M, Czech A, Kleizen B, Ostedgaard LS, Braakman I, Sheppard DN, Ignatova Z. Alteration of protein function by a silent polymorphism linked to tRNA abundance. PLoS Biol. 2017 May 16;15(5):e2000779.
  4. Cuppens H, Marynen P, De Boeck C, Cassiman JJ. Detection of 98.5% of the mutations in 200 Belgian cystic fibrosis alleles by reverse dot-blot and sequencing of the complete coding region and exon/intron junctions of the CFTR gene. Genomics. 1993;18: 693–7.
  5. Steiner B, Truninger K, Sanz J, Schaller A, Gallati S. The role of common single-nucleotide polymorphisms on exon 9 and exon 12 skipping in non-mutated CFTR alleles. Human Mutat. 2004;24: 120–9.


A pre-antibiotic apocalypse?

A number of years back I undertook a project researching novel small molecule inhibitors for bacterial RNA polymerase as antibiotic agents. Back in 2009 there was huge worry for the increased bacterial resistance to marketed drugs as there had been for many years prior. I had decided to have a look at recent publications and developments in antibacterial drug research for the purpose of this blog until last Thursday morning when I awoke to the media in a frenzy.

The mainstream newspapers, radio and TV were all discussing antibacterial resistance and the “pre-antibiotic apocalypse” that loomed. Surely, this has been in discussion for years? I realised that I too had perhaps become complacent to the advancement of antibiotics in recent years. So to sidestep the more sensationalist media stories I decided look at the issues and some of the facts behind the story.

The recent media storm comes from comments made by England’s Chief Medical Officer Prof Dame Sally Davies who warned that antibiotic resistance could spell the “end of modern medicine” and unless something was undertaken to address the problem a potential “pre-antibiotic apocalypse” could occur making currently routine operations very risky and put a stop to transplant medicine [1] [2].

These are strong comments indeed however to be honest an opinion that I feel the scientific community have held for a long time. When commencing the antibacterial project 8 years ago methicillin resistant staphylococcus aureus (MRSA) was big news with patients contracting infections in hospitals due to these methicillin resistant strains. The office for national statistics reported that in 2006 the number of death certificates mentioning S.aureus was 2,150 and of those 1,652 reported MRSA strains [3]. Although the number reported deaths due to MRSA fell in following years this was put down to improved policy, hygiene and protocol in hospitals rather than a reduction in the prevalence of the resistant strains or advancement in antibiotics.

Of course, this is only one example of resistant bacterial strains with pneumonia, gonorrhoea and perhaps more worryingly tuberculosis, HIV and malaria amongst other infections that are now increasingly harder to treat due to drug resistant strains. It’s estimated that around 700,000 people die per year worldwide due to infections of drug resistant strains, which include HIV, tuberculosis and malaria [5]. An AMR review: Tackling Drug resistant Strains Globally goes on to say that if the problem is not addressed a forecast prediction of mortality in 2050 indicates the number of deaths due to drug resistant pathogens could be 10 million a year engulfing the predicted deaths by cancer [5]. The World Health organisation (WHO) states that antibiotic resistance is “one of the biggest threats to global health, food security and development today” even hosting an World Antibiotic Awareness week (13-19 Nov 2017) to educate on safe use of antibiotics and the impact of misuse [4].

The antibacterial resistance issue is incredibly complex ranging from inability to create new innovative bacterial classes to the poor potential for economic return in research investment. Many factors have created the problem we now see today and these as need to be addressed for the situation to improve.

The issues of new antibacterial agents are underpinned by the need to create new innovative and novel drugs to counteract the potential for antibacterial resistance. In the past the pipeline of new antibiotics focused on modifying existing antimicrobial classes however this is simply a temporary fix and fail to address multiple resistance mechanisms.

In May of this year the World Health Organisation released a review of Antibiotic agents currently in the pipeline and specified the need for innovative products without cross resistance to existing antibacterial classes [6]

For a drug to be considered “innovative” it must fulfil one criteria of the following; being non cross-resistance to existing antibacterial class, a new chemical class, a new chemical target or a new mechanism of action. The review found that out of 33 drugs currently in the pipeline for priority indications 9 belong to 5 new antibiotic classes.

However the WHO review concluded that the current pipeline is “insufficient to mitigate the threat of microbial resistance” pointing to vast changes in policy, education and research to address the root cause of antibacterial resistance as well as the growing need for new drugs.

Antibacterial resistance has been reported for virtually all drugs currently on market and as well as multi drug resistant strains. This has largely been the blame of overuse and misuse of antibiotics in both humans and agriculture. As new classes of drugs are brought to market, without the education of patients and doctors, changes to policy of governments and organisations it is likely the issue will remain. As the bacteria evolution is at such a high rate it’s likely that resistance to new drug classes will be seen quickly if inappropriately used.

The AMR review: Tackling Drug resistant Strains Globally gives an in depth look at the complex nature we face with combating antimicrobial resistance with one key issue being the necessity for investment following years of under investment by companies and governments.

Between 2003 and 2013 only 5% of the total venture capital of pharmaceutical research and development was spent in antimicrobial research [5]. This equates to $1.8 billion of the total $38 billion spent. Pharmaceutical company’s no longer see antimicrobial research as attractive or that investment would provide an appropriate return for the risk.

Movement away from this research area can also be quantified by the lack drugs in the pipeline. In 2014 there were close to 800 oncology drugs in the pipeline in comparison with the 33 that are currently moving though for antibacterials’. Both the AMR and WHO reviews discuss the initiatives currently in place to encourage private and public investors into antibacterial research in an attempt to improve the attractiveness of the potential risk.

The problem of antibiotic resistance we face is incredibly complex and very real. Following on from last weeks news reports I believe the comments from Dame Sally, although illustratively put, to be nothing further then the truth. It seems little has moved on to truly battle the problem of bacterial resistance and only a combined effort of governments, healthcare professionals, pharmaceutical companies and individual people will get us away from the potential pre-antibiotic era that not only is frightening but a reality if we do nothing.

I started this blog with the best of intentions discuss the very important issue of antibacterial resistance in relation to the comments made in the media however I perhaps underestimated the highly difficult nature of the problem and the complex factors that drive it. So if you are interested I highly recommend the following articles for more detail:

WHO Review: Antibacterial agents in clinical development. May 2017

AMR review: Tackling drug resistant strains globally, May 2016

Blog written by Alex Ashall-Kelly






[5] AMR review: Tackling drug resistant strains globally, May 2016

[6] WHO Review: Antibacterial agents in clinical development. May 2017