Re: Antibiotic drug research and development
7 May 2012
Piccaud emphasizes an economic and business model to drive new antibiotic discovery as a key aspect of addressing the problem of antibiotic resistance. We suggest that an ecological perspective is perhaps more important and gives less grounds for optimism that investment in new drug discovery will make a major contribution.
In many ways the ideal target for antibiotic action is a critical step in bacterial physiology that has no parallel in mammalian cells. Penicillin is the classic example. Penicillin targets a critical step in the process of bacterial cell wall synthesis, a process that has no parallel in mammalian cells. Because there is no parallel in mammalian cells there is little dose related toxicity from penicillins. Unwanted effects are largely related to hypersensitivity and disturbance of normal bacterial flora of the gastrointestinal tract or mucosal surfaces.
As biological motifs are generally highly conserved in evolution the number of such ideal targets where mammalian cells have diverged very widely from bacteria is likely to be very limited. It is also important to recognize that there are many naturally occurring compounds (including penicillin) in the general environment that may disrupt critical steps in key bacterial pathways. As a result of this exposure natural selection has ensured that many bacteria that live in the environment exposed to these compounds have acquired enzymes or pumps or other systems to neutralize the effects of toxic compounds. We recognize this in clinical practice as intrinsic antimicrobial resistance.
With that perspective we should see that for human health care there were 2 very valuable aspects of pre-antibiotic era microbial biodiversity. These were (a) the existence of a limited number of points of major difference between critical pathways in bacteria and mammals (ideal targets) and (b) that most common species of bacteria that cause life threatening human infection had little in the way of neutralization systems to protect critical pathways from compounds such as the early antibiotics. In the pre-antibioitic era systems to neutralize antibiotics were of no survival value to bacteria that lived mostly in or on people and animals.
All of this explains why it was relatively easy to find those early magic bullets. In a few decades, the blink of an evolutionary eye, human activity has resulted in a profound transformation of pre-industrial microbial biodiversity. The widespread use of therapeutic antibiotics and indiscriminate use of other antibacterial substances ( dsininfectants and biocides) has made an environment both within the human body and at the interface between the human body and the environment (sewage systems) where there is intense selection pressures that have reshaped human pathogens so that they now have systems to protect those few and all important “ideal targets”. The indiscriminate use of therapeutic antibiotics, disinfectants and biocides are central to the problem but this is compounded by weak or non-existent infection control, increasing population density, environmental contamination with untreated sewage (contain antibiotics and GIT bacteria) and global travel to disseminate every resistance phenomenon that emerges.
The call for systems to support new antibiotic discovery is of course welcome. However, from an ecological perspective it is not clear that we can place too much emphasis on new antibiotics as “the necessary tools to fight antimicrobial resistance in the long term” or that we can expect there will be a “renewable pipeline of products” if only we work harder or work smarter. It is highly plausible that there is no other penicillin or tetracycline to discover. It may be that even with all the support that Piccaud rightly calls for that the best we can hope for is to find a modest number of substances that may be more toxic and less effective than the antibiotics we have been used to.
The existing classes of antibiotics are probably a non-renewable resource (like oil) – they are probably the best we will ever have – we must not create the expectation among policy makers that there is an economic solution that can create a pipeline for the future that will make up for our continued squandering of this remarkable natural resource.
Competing interests: None declared
NUI Galway School of Medcine, Newcastle Road, Galway, Ireland
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