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.

Bypassing Needle-Dependent Insulin Therapy in Diabetic Patients.

Modern Digitized Insulin Pump
Image credit to Tandem Diabetes Care.

Two weeks ago, we had a counselling session in the clinic for children with Type 1 diabetes mellitus (a type of diabetes that totally depends on taking an artificial form of the normal insulin produced in the body to be able to stay healthy and alive) when I rotated through the Endocrinology Unit of our Paediatrics department; these patients came along with their family members, and a pharmaceutical company that manufactures artificial insulin was also invited. Our consultant endocrinologist headed the counselling session, educating and re-educating these paediatric patients and their families on the management of their medical condition--diabetes--through lifestyle modification (taking the appropriate food, drinks and so on) and appropriate use of the injectable insulin: how many times to inject themselves with insulin in a day; on ensuring they take some insulin shots before meals; and so on.

Digitized Insulin Pump linked to
a Health Management Software on
a PC for patients and Physicians.
Image credit to Tandem Diabetes Care

These children, I must say, were learning from these periodic sessions evidenced by how they gave very detailed accounts of what they have learnt and the risks of not adhering to the guidelines given to them. But worried me as I sat among my fellow medical students that day was the constant pricking these children would have to endure every day to take their insulin because the only insulin therapy still available in Nigeria currently is the injectable insulin (variations exist such as the insulin syringes and the insulin pen which the invited pharmaceutical company displayed and educated the patients on how to make use of). Aside this, even the insulin pumps (with all the newest modifications they have undergone) that are common in developed parts of the world still require the patient to insert the infusion set under the skin and carry it around (hence, the patient has to always be cautious about some activities in order not to disrupt the inserted infusion set of the pump which would dislodge the pump from the body and pose health risk to the patient).

Afrezza Technosphere Inhalable
Insulin. Image credit to Mannkind Corp.

The highlighted worry above is not just the problem faced by diabetic patients in Nigeria alone, but the world over. Though, research (such as artificial pancreas, pancreas transplant and so on) is intense to address this major problem of invasive insulin self administration, something immediate need to be done to reduce the need for needle pricking several times a day by people with diabetes, especially Type 1 (people with this type of diabetes may die if the level of sugar in their blood goes far above or below a certain level, and hence a standby insulin at all times is very essential). And it seems that there is hope (though for now not for Nigerians with diabetes) as the US Food and Drug Administration, FDA (the US version of Nigeria's NAFDAC), on the 27th of June this year approved an inhalable form of insulin called Afrezza designed by the US pharmaceutical company Mannkind Corporation, after the FDA advisory panel met in April this year and over 90% of the members voted in favour of the inhalable insulin, following data gathered from the clinical trials confirming its efficacy was carried out in over 3000 patients with both Type 1 and 2 diabetes (Afrezza is not the first attempt at making inhalable insulin: the pharmaceutical company Pfizer did come up with its own inhalable insulin called Exubera developed by a company Nektar Therapeutics far back in 2005 but the product was pulled out of the market in 2007 because of the lung problems that ensued in some users, the high cost and lack of benefit over the injected insulin). The FDA has mandated that Afrezza be subjected to post-market study to monitor possible long-term outcomes, one of which is the possibility of some patients having lung cancer from the use of the product.

The Afrezza inhalable insulin uses what its manufacturer calls the Technosphere technology (particles in
 powder form made up of biologically non reactive chemicals that carry the artificial insulin to the lungs once inhaled, and they completely separate from the insulin in the lungs to allow rapid absorption into the blood) to deliver inhaled insulin to the lungs where the insulin is absorbed rapidly into the blood, reaching maximum level between 15 and 20 minutes, hence preventing any imminent sugar overload of the blood, especially after meals. Afrezza inhalable insulin is contraindicated in patients who smoke or have asthma, or chronic obstructive lung diseases such as bronchiectasis.

The major setback though is that the inhalable insulin cannot replace the long-acting insulin needed by Type 1 diabetic patients, meaning that these patients still need to inject insulin, but probably once a day, while using the inhalable insulin before or a few minutes into their meals. Now, this is where something can also be done, maybe not immediate.

Women have the option of using the implantable contraceptives (which are inserted surgically, under local anaesthesia so that no pain is felt, deep into the skin of the inner part of the upper arm or thigh) which deliver artificial oestrogen and progesterone at rates required to prevent pregnancy for at least 3 years. Something similar, I think, can be done in the case of insulin: we can have insulin implants designed to release insulin at rates required for the basal level in these diabetic patients. This will replace the long-acting insulin injection and last for probably up to 3 years before it could be replaced; there is still pricking, but this time it is probably once in 3 years and then it is done under local anaesthesia, so the patient would not feel any pain. I believe work is ongoing on something like this.