Scientists Begin to Unlock Some of the Keys to Drug Resistance

World Health Organization meeting on Drug Resistance in Leprosy.
Image credit to National Leprosy Eradication Programme

Some time ago I talked about the threat that drug resistance by disease-causing microorganisms poses to mankind if nothing is done now to tackle it. A few days later, the World Health Organisation echoed the same warning and emphasized the need for urgent action in finding new and potent ways to thwart this potential (and what I call) global terrorist attack by these disease-causing microorganisms as they continue to challenge our God-given right to replenish, conquer and dominate the world (for the animal activists out there, don't misunderstand me: I'm not talking about total annihilation of all microorganisms because there are the good guys among them who are minding their own business--the normal flora of our environment--and who are not challenging our God-given rights).

One of the disease-microorganisms that has developed what I call smart resistance to drugs which previously dealt with it is the tuberculosis-causing organism called Mycobacterium tuberculosis. This microorganism has evolved into to variants now known as Multi-Drug Resistant (MDR) and Extensive Drug Resistant TB that is unaffected by most of the first-line and second-line anti-TB drugs, requiring combination of anti-TB drugs from more than one class before the patient's condition can see any improvement. This type of treatment, to be effective, may take up to one year or more, meaning more cost and more side effects of these drugs to the patient (and the patient will have to pay for other drugs needed to counter some of the side effects): this places a big burden on patients in parts of the world where TB is more likely to flourish: the poor populace of the world where access to health care is very limited. In addition to this problem, a case of a variant of a particular disease-causing bacterium resistant to all known potent antibiotics has been documented.

Crystal structure of the LptDE complex.
Image credit to Nature.

But rights (our God-given rights), I believe, come with the necessary provisions and weapons to defend and protect them. According to a research published in the journal Nature, scientists have unraveled the structure and mechanism with which a group of drug-resistant bacteria, termed gram-negative, build their exterior coating wall that, over generations of mutations, has become impermeable to most antibiotics and also able to conceal the bacteria from the attack of its host (human) immune system. Scientists used the Diamond Synchroton facility in Oxfordshire, Oxford, which produces intense X-rays about 10 billion times brighter than that the light from the sun, to study crystalline forms of the isolated protein samples from the exterior of these bacteria at the atomic level. The result was an atomic-scale revelation of the structure of a protein complex called LptDE, in the cell wall of the bacteria. The detailed information gathered was then used to create models to simulate how this protein complex assembles molecules called lipopolysaccharide in the bacteria cell wall from the inside of the organisms; it was also found that the final stages of this assembly could be attacked from the outside using new antibiotics to shatter the whole assembly process and leave the bacteria exposed without a covering and vulnerable to the environment--the host immune system attack. One more good news is that the protein complex LptDE has been found to be almost the same across a broad range of gram-negative bacteria that cause a large number of diseases such as meningitis, meaning that designing a class potent antibiotics against this key structure could be the master key to treating these diseases. The way forward now, according to experts, is to start exploring this great opportunity to design novel drugs that can inhibit the mechanism of the protein complex, LptDE.

Diamond Light Source of the Synchroton Facility in Oxfordshire, Oxford.
Image credit to Diamond UK.

While this is a great basic and fundamental discovery and has brought much to hope for, isn't there a possibility that sustained offense against the LptDE mechanism (when we develop antibiotics against it) can trigger the need for these bacteria to undergo mutations that will alter some parts of the structure of the component proteins involved in the assembly work to render the designed antibiotics useless? There was a time when our current antibiotics were working wonders because they targeted what were found then as structures and mechanisms crucial to these microorganisms' survival; but the same crucial targets have become smart at adapting to our offenses.

Simulated model of the Lipopolysaccharide Assembly.
Image credit to Nature.

My point is that we've got to have many potent options (like I said in a similar post) at dealing with these microscopic bad guys. In addition to leveraging on this current discovery, and also embarking on a suggestion I made in a similar post, I believe there may be special areas in these microorganisms that are very vital to their survival and at the same time do not undergo mutations at the genetic level because any alterations in the molecular structure of these vital areas would destabilize the microorganisms. Efforts should be geared towards identifying these areas in the global MutaGenome Project-areas I will want to tag Rigidity Importance Sites in drug-resistant microorganisms because they are very important to their survival but do not undergo mutations no matter the changes in the organisms' environment. This will enable the development of drugs targeted towards the translational outcomes (protein structure) of these Rigidity Importance Sites (RIS) in the DNA of the microorganisms. And one way to do this could be by creating models of the genome of some of these microorganisms and try to simulate their genomic replication, transcription and translation using data gathered from accumulated laboratory investigations and all possible effects of environmental changes on their genome over several generations--this I believe may reveal these areas of the genome that hardly undergo mutations, irrespective of the extent of external threats, but are very very crucial to their survival. Drugs designed against these Rigidity Importance Sites will be extremely potent at eradicating these disease-causing niggers, and any attempt to develop resistance to the drugs by mutations will be fatally detrimental to them; hence, we have a double-edged sword against them.

And we'll keep on exercising our God-given fundamental rights to dominate over disease-causing microorganisms because there is hope and we are smarter than they are.

Drug Resistance: Man's greatest threat in the survival of the fittest.

Drug Resistance. Image credit to ZME Science

The rate at which microorganisms harmful to our health are adapting to the various treatment modalities (drugs) currently available is very alarming and dreading. It is unfortunate to say that it seems that we're not one step ahead of these tiny, invisible-to-the-naked-eye organisms that are behind the various diseases that have affected humans since the beginning of history.

Prof. Randy Schekman, Nobel Medicine Laureate. Image credit to Nobel.org

Why it seems that we in the medical field are not one step ahead of these tiny organisms there can be many reasons. Topmost among them is the lag in basic fundamental research. Late last year, Professors Randy Schekman, James Rothman and Thomas Suedhof who jointly shared  the 2013 Nobel Prize in Medicine lamented over what they termed a neglect on basic research when the the US National Institute of Health created a Centre for Advancing Translational Sciences. In the words of Prof. Suedhof "......we don't have anything to 'translate' because we just don't understand the fundamental diseases of the brain....". His opinion is buttressed by the fact that there have emerged strains of the tuberculosis-causing organism, Mycobacterium tuberculosis, that are resistant to all known anti-TB drugs; the same could be said of some strains of the Staphylococcus species which cause myriads of diseases in humans. The problem here is that even the most recent drugs used in eradicating these organisms have the chemical structural framework and pharmacodynamics (a drug's way of carrying out its work in the body) that was developed in the 1960s and 70s; and there is no enemy being fought by its adversary with the same tactics over 4 to 5 decades, who will not evolve defence mechanisms that will one day confer on it total immunity from such tactics and also allow it to mount fatal attack on the adversary.

Another reason for this lag in our effort to be ahead of these disease-causing organisms is the lack of a large scale, collective and multidisciplinary undertaking to study in minute details the various ways in which these organisms evolve drug-resisting defence mechanisms. And what I mean here is an undertaking similar to the global Human Genome Project that saw to the successful sequencing of the whole human genome.

Having outlined these two reasons, I would now set out suggestions as regards how we can totally be in control of this fight against these human disease-causing organisms.

Prof. Kary Mullis. Image credit to NNDB

While it may seem that basic research in the area of drug development is not blossoming as we expect it, some tiny silver linnings I can fathom from some corners around the world. The one that comes to my mind is the work being done by the Nobel Chemistry laureate, Prof. Kary Mullis (he won the 1993 Nobel Prize in Chemistry for his invention of the Polymerase Chain Reaction, a technique used to create billions of a single DNA segment in a few hours).His concept of Altermune which he explained on the TED talk show conference is something that will give our tiny, microscopic adversaries a surprisingly lethal blow. Prof. Kary Mullis is taking a new, novel and radical approach towards fighting drug resistance in bacteria and other disease-causing microorganisms. The Altermune concept is a technique that uses an artificially synthesized molecule called Alphamer or Altermune linker to re-direct our own immune system to destroy these invading bacteria and other disease-causing microorganisms. An Alphamer or Altermune linker consists of a short sugar chain (an alpha galactose oligosaccharide)---which normally is not attacked by the body's immune system despite the immune system producing antibodies in response to its exposure---linked to a synthetic DNA segment called an aptamer with a specificity for only a particular strain of a virus or bacterium such that once this particular microorganism (which may be resistant to all available antibiotics, antiviral agents and other drugs in this case) invades the body, the aptamer segment of the Altermune linker binds to it and the antibodies produced in response to the galactose oligosaccharide exposure (but which does not harm it) will in the process be exposed to fresh food (the invading disease-causing organism), destroying it, both personally and by inviting other hungry guys of the immune system---the macrophages, the cytotoxic T cells and the complement system. Prof. Mullis has tested  his new work on mice infected with a strain of Staphylococcus aureus resistant to even the most potent antibiotic---this became his enemy because it killed his professor friend---and recorded almost 100% wipe out of this bacterium from the blood of the mice after a set period unlike in the controls which used various antibiotics such as doxycycline; further studies are going on in other animals such as chicken infected with the flu virus, using Altermune linkers designed for such microorganisms. Human trials will likely start soon, especially if there are emergency cases where the patient could be at the point of death because every other available option has been explored with no results. And this will unleash a whole new field of fighting against microorganisms causing disease in humans (if this works out well in human, Professor Mullis may win another Nobel Prize but this time in Medicine in about ten to fifteen years' time).

Alphamer or Altermune Linker. Image credit to Prof. Kary Banks Mullis

While this is ingenious, there is also great wisdom in exploring other ways so as to have several novel strategies for attacking these current-drug-resistant microorganisms. And I think one possible way to do this is to extend the kind of global interdisciplinary collaboration enjoyed by the Human Genome Project to the study of drug resistance in every known disease-causing microorganisms, not just some small scale collaborative studies that are obtainable currently (however, this is not condemning small scale collaborative researches as they form the foundation for large scale collaborations). Drug resistance by microorganisms comes into play when these organisms undergo mutations. Mutation is a change in the framework of some portions of an organism's genetic architecture responsible for encoding proteins that make up the structure and function vital to its existence and continual survival in the face of factors (drugs and other therapeutic strategies) that threaten them. What if we have what I call the global MutaGenome Project in which researchers from all fields will collaborate at a global scale to map all the genetic mutations in all known disease-causing organisms over generations? These mutations will then be graded on a conventional scale, depending on the extent to which their phenotypic manifestations cause diseases in humans and mount resistance to our therapeutic strategies. By engaging in such large scale endeavour, we create what I call a mutagenomic database from which patterns in which these genetic mutations occur both among similar organisms and across different organism can be outlined, hence enabling us to use mathematical tools---such as the Nash Game Theory, Permutation and Combinations and so on already employed in evolutionary biology---to predict possible future genetic mutational patterns, outcomes, and understand clearly the working dynamics between each particular threat at the molecular level (in the form of therapeutic modalities) and mutational response (resistance development) in these organisms. This could then lead to different predictive therapeutic designs for a particular bacterium over time in response to its possible resistance development options. With this approach we can have centres for MutaGenomics and MutaGenomic Therapy (Mutational Genomics) in universities and research institutes around the world designing novel therapies for various diseases.

This is a very daunting and big ambition. But we did it in the Human Genome Project, and we can also do it in the global MutaGenome Project.