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.