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


[1] http://www.independent.co.uk/life-style/health-and-families/health-news/antibiotics-resistance-apocalypse-warning-chief-medical-officer-professor-dame-sally-davies-drugs-a7996806.html

[2] https://www.theguardian.com/society/2017/oct/13/antibiotic-resistance-could-spell-end-of-modern-medicine-says-chief-medic

[3] https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/deaths/bulletins/deathsinvolvingmrsa/2013-08-22

[4] http://www.who.int/mediacentre/factsheets/antibiotic-resistance/en/

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

Click to access 160525_Final%20paper_with%20cover.pdf

[6] WHO Review: Antibacterial agents in clinical development. May 2017 http://apps.who.int/iris/bitstream/10665/258965/1/WHO-EMP-IAU-2017.11-eng.pdf?ua=1

19th RSC/SCI Medicinal Chemistry Symposium

I recently attended the 19th RSC/SCI Medicinal Chemistry Symposium held at Churchill College, University of Cambridge (UK) – this was the first medicinal chemistry symposium I have attended since joining the field approximately 3 years ago, and it certainly didn’t disappoint. The symposium was held over 4 days, with the first day dedicated to a medicinal chemistry workshop for early career researchers (those with 5 years or less experience within medicinal chemistry). I found the medicinal chemistry workshop a good learning experience – we started from a series of hits and had to try to progress at least one compound into a preclinical candidate. The team that I was working in came 2nd out of 7, just being pipped to the post for 1st place.

Mark 1

Introduction to Technical Programme

 The technical programme started on the second day, and from the outset the talks were quite diverse with projects from many therapeutic areas being discussed, with several first disclosures being presented. There was a dedicated Neglected Tropical Diseases session that was webcast live through the RSC website, highlighting a range of diseases that require much more attention than they currently receive. Although a lot of great medicinal chemistry was discussed, it was a talk by Gianni Chessari from Aztex Pharmaceuticals that I found particularly fascinating. Gianni described a fragment-based screening approach using PyramidTM for the discovery of inhibitors of apoptosis proteins (IAP). He described structure-based hit optimization utilizing computational and NMR studies – by analysing the confirmation of their hit compounds, they were able to increase binding affinity and subsequently develop a potent non-peptidic IAP antagonist ASTX660 that is currently being tested in a Phase 2 clinical trial.

Overall I found this conference a great learning experience and a good opportunity to meet like-minded individuals from both academia and industry – I particularly enjoyed the opportunity to network at the Gala Dinner in the impressive surroundings of St John’s College!

Mark 2

Gala Dinner at St John’s College

Blog written by Mark Honey





Alzheimer’s Disease – Dopamine first

Alzheimer’s disease (AD) is a progressive neurodegenerative brain disorder that causes a significant disruption of normal brain structure and function. At the cellular level, AD is characterized by a massive neuronal loss that primarily affects the hippocampus and cortex, mainly due to the accumulation of intracellular neurofibrillary tangles and extracellular amyloidal neuritic plaques.


Fig.1 -Schematic representation of AD-related mechanisms (Medicinal Research Reviews · 2013)

The hippocampus is a critical brain structure for memory development and damages in this area are believed to be the primary cause for memory loss in AD patients. However, progressive structural alterations in different brain areas may play a pivotal role in the worsening of memory and cognitive dysfunctions. Consistent with these observations, several alterations in the dopaminergic system have been reported in AD patients, together with reduced levels of dopamine (DA) and its receptors. Moreover, DA is a well-recognized modulator of hippocampal synaptic plasticity and its binding to dopaminergic receptors in the dorsal hippocampus is a major determinant of memory encoding.

A recent study published on Nature Communications (DOI: 10.1038/ncomms14727) highlighted how, in a mouse model of AD, at a stage when no Ab-plaque deposition, hyperphosphorylated tau tangles or any sign of neuronal loss in cortical and hippocampal regions has yet occurred, a specific apoptotic process is taking place in the dopaminergic neuronal population in ventral tegmental area. The loss of dopaminergic neurons is paralleled by a reduced outflow of DA in the hippocampus, thus contributing to the deficits of hippocampus-dependent memory and synaptic plasticity, as well as impairment in reward processing. These symptoms are improved by stimulating the dopaminergic system with the administration of L-DOPA or the reduction of its endogenous degradation.

Although the abovementioned process has been observed in an experimental model of AD, it might provide an interesting explanation to recent evidences in AD patients, indicating that the clinical diagnosis of dementia is associated with early non-cognitive symptoms, such as depression and apathy. Based on that, changings in the mood of AD patients would be not a consequence of this pathology but rather an alarm for an early stage development of AD, confirming the strict correlation between depression and subsequent loss of memory.

This picture is somehow symmetrical to what researchers involved in Parkinson’s disease and although the molecular mechanisms underlying early dopaminergic neuron degeneration in the ventral tegmental area remain to be elucidated, these results suggest DA as an important player to consider in the context of AD.

Blog written by Samuele Maramai