Antibiotics – time for a rethink?

by admin on November 19, 2012

MRSA Bacteria
Last week Professor Dame Sally Davies Chief Medical Officer issued a warning about prescription habits and the dangers of rising bacterial resistance associated with excessive and inappropriate use of antibiotics. This is not a new issue but her stark reminder is relevant globally including the US.

Given antibiotics are arguably the biggest factor in the extension of life over the past century then this is no trivial matter. It has seen the rise of resilient strains of TB amongst other bacteria including the well documented hospital infections MRSA and C.Difficile.

Existing prescription habits

The accepted practice is to issue established broad spectrum antibiotics in primary care and retain the big weapons of novel action antibiotics in reserve for treatment of resistant cases.

Network pharmacology as a new approach to drug discovery offers telling new potential to this battle and poses fresh questions of this accepted clinical practice for antibiotic prescription.

How antibiotics work

A lot of antibiotics are incomplete killers of bacteria, the well worn analogy is they hold the arms of the bug behind their back while the immune system beats them up. Accepted theory is that antibiotics work by disrupting the bacteria based on their binding with a single critical protein target which damages the bacteria. Bacteria replicate rapidly meaning successive generations can evolve quickly adjusting their systems to make the protein target of the antibiotic no longer essential for their well-being.

An alternative theory is that the resistant strains already exist and the antibiotics kill the vulnerable leaving the non-susceptible forms to replicate and be the predominant source of the next generation of bacteria which are consequently resistant.

Irrespective of which or both of the above explanations reflect the reality, resistance stems from variations in the wiring of the proteomic systems of bacteria. These complicated protein systems are responsible for biological function in all life, genes are responsible for the creation of the parts but are one step removed from the protein systems that are the engine of life. Complex systems science is a new discipline which analyses such complicated systems to establish the points critical for their integrity (survival) and/or for specific biological functions. This discipline has established that systems such as the proteome of bacteria are very robust to single points of intervention meaning development of resistance against antibiotics which work in this manner, is easier.

New generation antibiotics

The requirement is arguably for agents that more rapidly and completely destroy bacteria (without adversely impacting the human host) on a basis which is difficult for bacteria to evolve around. This is where network pharmacology comes in. Only through analysis of the bacterial proteome using these new techniques can the synergistic points in these systems be established. The consequence of this is that bacteria can be damaged or destroyed much more completely than is the case with existing antibiotics. This is achieved through binding simultaneously to carefully selected proteins which synergistically have a profound impact on the bacteria. Such multi-target modes of action for antibiotics are more difficult for bacteria to evolve around and develop resistance to.

Network pharmacology as an approach brings the potential to rapidly and affordably develop an armoury of effective new antibiotics for specific bacteria that kill the bacteria quickly and against which development of resistance is slow and more unlikely.

New generation antibiotics, new generation clinical practice?

Such a capability has consequent implications for accepted clinical practice as described above. If such narrow spectrum antibiotics are created is it not better to use these in the first line of primary care as they are more effective and less likely to see the rise of resistance? It would require the development of faster and easier point of care diagnostics but again network pharmacology offers distinct advantages for this. Broad spectrum antibiotic misuse and over use can lead to an increase in resistance of a range of bacteria including the disruption of digestion by attacking friendly bacteria in the gut. This can have serious implications for the weak and vulnerable. The mode of action of these new age antibiotics would be understood in detail and differs from those of existing antibiotics allowing them the older drugs be ‘rested’ and kept in reserve.

For an understanding of how such antibiotics can be developed then read the previous blog on Ash trees and treating dieback disease as the approach is very similar. The first drugs from this method are now in development and the results to date are cautiously validating the promise. The authorities would do well to focus some attention and resource on this fledging new discipline and substantial impact it can have on the antibiotic issue and garner expert opinion of the clinical practice implications it creates. In the meantime Professor Davies warnings look pertinent wherever you are.

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Roulette wheel
Biotechnology investment is not for the faint hearted with the potential to make a fortune or to loose the lot making casino comparisons understandable.

We believe network pharmacology will have a major positive impact on biotechnology investment by allowing extremely lucrative but, to date, evasive new treatments become a reality. As a largely unknown or poorly understood new discipline in drug discovery the pipeline of drug candidates in pharmaceutical and biotechnology companies have not been created by the methods of network pharmacology, with a few arguable exceptions.

Does this mean all the drug candidates in company pipelines are not worthy of investment? The truthful answer is nobody knows but the fact that some make it and create large rewards but the vast majority fail in the clinic is indicative of the present risk/ reward balance.

What network pharmacology can bring to investors is rigorous scientific perspective and context. The bad news is most of the information needed for a proper assessment is either not available or not released into the public domain. (Interestingly with the right tools this information can theoretically be obtained from public sources without breach of patent or stock market rules but that’s a whole different discussion.)

Without protein interaction data at the systems level; the ability to do analysis at the systems level and compound network pharmacology information then insight is limited. However there are some generic rules of context that may help investors;

Basis of biological function
Remember biology functions as a result of complex protein interaction systems. This is the context you are looking for in terms of any claims of how the drug is reported to work as well as safety issues.

Beware simple targets
A mode of action consisting of a single target in a biological system is statistically very unlikely to be successful with complex or multi-factorial disease. Relevant protein system context is the key, tread carefully when drug candidates are based on:

  • Gene information without protein system context. Genetic trends observed in the disease state do not necessarily mean they represent a target for treatment of the condition.
  • Protein pathways generally only form a small part of a protein system. Owing to the rules of complex systems science even the most beautifully described protein pathway provides virtually no insight into the impact the chosen mode of action will have at the all important systems level.
  • Targets consisting of a single gene, gene mutation or single protein are likely to be too simplistic to be effective according to the rules established in complex systems science.

Development stage is not necessarily directly linked to risk
Early stage drug candidates are not necessarily lower risk than later stage drug candidates. Especially if greater context is given as to the systems impact of the drug in the relevant biological systems.

Pre-clinical context
Context is also important for judging pre-clinical results. Does the model chosen have a track record of being representative of the human equivalent and/or proven to be predictive of efficacy. For example not all cancer cell lines results carry the same importance.

Clinical trials – design as well as results
Clinical trials serve the dual purpose of meeting regulatory requirements and providing key information about the drug candidate. The value of the information is reliant on the design. Drug Baron have outlined the key issues in the context of Phase II data.

Is delivery feasible?
What is the location of the proposed site of efficacy and are there difficulties delivering the therapeutic to that site? Have they a plan for addressing delivery and what is the evidence it will work?

Look under stones re safety
Do the compounds have any safety history? As well as clinical and pre-clinical safety data is there any further information on:

  • Other drugs with the same target having safety issues.
  • A wider spectrum of protein and genetic interaction of the drug candidate than just the headine ‘target’.

The above points will be unpacked in greater detail in future posts.

We are not investment experts and leave commentary on the commercial issues of specific companies such as cash, licensing, strategy etc to the legions of experts better qualified for this.

In a recent article the argument is made that biotech is in danger of becoming the next dot com bubble. We believe that the potential is there for huge investment returns but without a switch to a basis of confronting the realities of complexity and how biology actually works then sadly bust looks more likely than boom.

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