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Neurocascade Events and Lyme

By

Tom Grier

The human brain is by far the most complex and least understood organ of the body. The brain stores and organizes data far more efficiently than any computer in the world, it isolates itself from the rest of the body including the immune system, and acts as an endocrine organ sending hormones and chemical messages into the far reaches of the body affecting every cell in our body. When the brain is sick or injured our whole body is affected.

Our brains allow us to use our muscles by shear will of thought. The electrical impulses we command are rushed through our spine and filter through our limbs to the exact set of muscles we need to control. Equally important the brain will take care of our basic bodily needs like breathing, and heart rate, when we are unconscious.

Our brain works when we sleep, but requires rest. We see images when we open our eyes and again when we dream, and each image that we see is a construct of the brain. Our thoughts, our dreams, our memories are all stored patterns within our brain. So what happens to the essence of us, when the brain is damaged?

More specifically what can we expect when our brain is traumatized by a bacterial infection of the brain as can happen in Lyme Encephalitis?

The bacterium that causes Lyme disease is a highly motile spirochete within the Borrelia family of bacteria. This is the same group of bacteria that cause Relapsing Fevers around the world. Like other Relapsing Fever bacteria, Borrelia burgdorferi the causative agent of Lyme disease has both an affinity for the brain and a mechanism to penetrate into the brain.

Other neurogenic strains of Borrelia that cause Relapsing Fevers in Africa can be deadly within mere weeks of entering the brain. While Lyme disease may be a bit more subtle upon penetrating the brain, its silent and insidious invasion may be the reason that brain involvement can and is often be overlooked by physicians for months or even years in neurological Lyme patients.

Just like the spirochete that causes syphilis can remain active within the brain for decades in tertiary Syphilis, there is equal cause for concern that the Lyme bacteria can also become a sequestered unwelcomed interloper to the central nervous system.

How does the Lyme bacteria enter the brain when the blood brain barrier fights against foreign invasion?

(The blood brain barrier is simply a network of capillaries that selectively feeds nutrients to the brain. The walls of the capillaries in the blood brain barrier are so tight, that they do not allow most things from the blood to pass into the brain. Also the vessels respond differently from the peripheral vessels and selectively allow some things into the brain. Some things pass through freely but many things like vitamin-C requires the brain to expend energy to pump it across the cell membranes. This selective process probably prevents infections of the brain on a weekly basis.)

Once the Lyme spirochete enters the peripheral blood circulation through an infected tick bite, the bacteria fights to escape the confines of the blood vessel walls. It seeks a better place to live and thrive. One such place is the human brain.

The spirochete's motility allows it to swim in the blood stream until it lodges a wiggling tip into a endothelial cell junction, where it bores between endothelial cells lining the capillaries and causes a specific inflammation and irritation that causes the endothelial cells to release digestive proteins that create holes within the capillary bed. There is probably a receptor involved in this attachment and irritation.

(Borrelia burgdorferi activates the tissue plasminogen activation pathway (PAS) and soon other enzymes are involved in degrading the integrity of the vessels walls. It has been observed the proteases such as basement laminase, urokinase, metallomatrix proteases, the fibrinolytic pathway, and lipases all play a role in degrading human brain micro-endothelial cell integrity. In mice and other animal models the PAS pathway in Lyme disease plays a critical role in developing carditis and other inflammatory states including arthritis.)

In 1989 experiments were done using umbilical cord vein to show that Borrelia burgdorferi attaches tip first to endothelial cells and microscopic examination found holes near the areas of attachment. If these vessels were within the heart or brain it would be clear that there is nothing to stop Borrelia and other blood stream components from entering those sites. In the case of the brain, allowing bacteria and white blood cells access to the brain is setting up the brain for a series of events to occur which we can call neurocascade events. This is where one event will trigger another, which in turn will trigger another and so on until a small nonsymptomatic event becomes noticeable.

To see if Borrelia burgdorferi truly breaks down the blood brain barrier, several animal experiments were done. Since blood albumin protein should not be in the cerebral spinal fluid (CSF) researchers tagged normal albumin with radioactive Iodine. In mice, hamsters, and dogs without infection the radioactive Iodine never penetrated into the CSF of the normal control animals. But when the animals were infected with Lyme disease, within mere hours the blood brain barrier became permeable and radioactive iodine was found within the CSF of infected animals usually for about two weeks following initial infection. This window of permeability certainly gives ample time for the Lyme bacteria to establish itself within the brain. Detailed collection of CSF from recently bitten lyme patients reveals that subclinical infections of the CNS occurs often before the infection in the body is even detected.

Before we talk about the neurotoxic effects of Borrelia burgdorferi within the brain, lets first look at some other neurocascade events that occur in acute brain trauma and repeated brain trauma such as in sports accidents like soccer, football and boxing.

Repeated concussions in football players and boxers can cause a slow onset of a syndrome sometimes called Pugilistic Dementia, or Sports Related Encephalopathy. Common symptoms begin months to years after injury occurs and usually includes: headaches, muscle twitches, tics, sensitivity to bright lights and loud noises, inability to retrieve words, loss of time, depression, suicidal thoughts. Later these symptoms can progress to fatigue, lethargy, loss of interest, severe depression, Parkinson-like tremors, loss of motor control, and overall slowness, and finally dementia.

An interesting comparison between Lyme encephalitis and Pugilistic Dementia (besides sharing similar symptoms) is that both patients can have global-cerebral-atrophy years after their initial trauma. In other words the brain shrinks, and appears to have lost the ability to properly repair damage that accumulates over many years. These abnormal MRIs of the brains of boxers and Lyme patients may be caused by different mechanisms, but the end result can appear similar in both the symptoms and pathology of the two conditions.

No one knows if once brain damage is allowed to go this far in Lyme patients with global cerebral atrophy, if that kind of damage can be improved or repaired? The best strategy is to never allow neurological symptoms in early Lyme patients to go unabated and untreated for fear that brain damage caused by persistent neurological Lyme cannot be completely undone.

So what happens pathologically in acute brain trauma and in Lyme encephalitis? When the human brain endures a concussion the brain bounces on the inside of the skull and a massive number of brain neurons fire all at once. This massive electrical discharge is like a focal miniseizure. For a moment those brain cells cannot relay nor store information. It is equivalent to having a part of the brain that is essentially switched off. It is like a short circuit in a computer chip. For example if the visual processing center of the brain is shut down by trauma you may be temporarily blind or have difficulty processing visual information.

These overexcited traumatized neurons make matters worse because they rapidly release an excitatory neurotransmitter called glutamate. The free glutamate rushes to nearby neurons and latches onto a neuron receptor called the N-methyl D-asparate receptor and over excites the neuron to repeatedly fire.

NMDA receptor stimulation causes a massive outpouring of potassium out of the neurons. To electrically compensate and balance the polarity of the neurons, calcium has to rush in. Its like punching a hole in a submarine: air rushes out and water rushes in only here the potassium rushes out of the cells and calcium rushes in.

The problem with this is that the calcium plays a different role inside a neuron and it literally clogs up the mitochondria of the cell. The mitochondria are what produces energy for the neuron. The calcium influx stops the production of glucose within the mitochondria of the neuron at a time when brain cells are screaming for more glucose to power all the cell repairs and to repolarize by using energy to rebalance the potassium and calcium. This takes energy that is not available. Without the extra glucose the neurons become dysfunctional, and can die without energy to operate. As the cells die their breakdown further adds to the cascade of brain damaging events.

In mild cases the brain compensates by using different parts of the brain to think and function and some individuals may feel minor ill effects from a concussion and can be quite functional. But over time with repeated damage or larger injuries these cumulative injuries can become devastating.

In Lyme disease we have a slightly different but similar scenario. Just as the Lyme bacteria can penetrate endothelial cells, Borrelia burgdorferi are directly neurotoxic upon contact with brain neurons and also have a negative effect on the glial cells trying to repair brain injuries. Just as they stimulate digestive enzymes in blood vessels, B, burgdorferi is known to stimulate similar enzymes that attack neurons and glial cells.

Once the Lyme bacteria enter the brain they continue to divide and become entrenched within the brain. Borrelia bacteria activates the macrophage and induces it to produce quinolinic acid in the brain. Quin-acid similar to glutamate in its affect, is also an NMDA receptor neuroexcitotoxin.

As Borrelia causes brain cells to die they to would release glutamate adding to this sequela. But unlike an acute brain injury, a brain infection starts small and grows larger with time. The inflammation increases and the damage grows and spreads.

As inflammation within the brain increases so do cytokines such as tumor necrosis factor alpha, and interlukin 1 and Il6. These in turn these lymphokines further increase the permeability of blood brain barrier allowing even more blood born agents to enter the brain.

In studies that looked at antibiotic treatment of meningitis in infants, it suggested that the presence of high dose antibiotics could break down the bacteria within the brain and cause even more inflammation. The immune system responds to the new flood of internal bacterial antigens and produces more inflammatory more cytokines.

(Notice that at no time is there mention of any endotoxin or bacterial toxin being release. To date there is no study or evidence to suggest that neural herxheimer reactions are caused by bacterial toxins, but rather is the host's immune response to bacterial antigens.)

The result can cause brain edema, intercranial pressure (especially in kids) and focal areas of demyelination. As cells die potassium rushes out, calcium rushes in and mitochondria are choked and clogged and energy demands climb exactly when glucose cannot be produced by the brain cells and the starving brain cells become ineffective and cease to function properly and sometimes die.

(In rat brain studies live Borrelia killed brain brain cells but dead Borrelia did not have the same affect. However the dead bacteria did stimulate cytokine production.)

It has been noted that in patients with chronic fatigue syndrome that the patients have higher glucose demands within their brains and have some cognitive improvement when glucose levels are artificially increased. In the case of diabetics with chronic fatigue syndrome, some have reported having more mental clarity at higher than normal blood sugar levels. This is something that normally causes sleepiness in a normal patient without CFS. Although the mechanism is unknown a model that prevents energy metabolism in the mitochondria seems to fit the clinical picture of cognitive dysfunction and fatigue in Chronic Fatigue Syndrome.

Another similarity between Lyme and Sports Related Dementia, is that global cerebral atrophy can occur decades after the initial trauma. It has been reported that severe acute infections of the brain with parasites, viruses, and bacteria including Lyme, can cause the brain to shrink in size over time. The short guess is that the brain after severe trauma loses its ability to repair itself as effectively as a brain that has not received physical trauma. The loss of neurons, and support cells over time results in brain atrophy, but much more research is needed both for cause and treatment.

Dr. Christopher Giza at UCLA showed clearly in rats that rats that had better developed cerebral cortex's were able to perform cognitive tasks better after repeated brain injuries. How do you build a better cerebral cortex? A thicker more complex cerebral cortex is obtained either by a lifelong pursuit of intellectual exercises to build stronger more interconnected neural networks, or by having good genes. In other words if you start with more brain power before a brain injury you retain more and recover better afterwards.

The question for Lyme patients suffering from encephalopathy following Lyme disease is: Can anything be done to minimize the impact of brain injury during treatment and recovery?

The answer is we just don't know. It doesn't help matters that comparative data in brain recovery post infection is a very difficult thing to collect, collate and assess. But in theory we do have a couple of options that have not been explored or evaluated.

The first consideration is earlier and more aggressive antibiotic treatments for Lyme disease to assure that once antibiotics are withdrawn that there is no continuing brain involvement by active infection or metabolically inactive infection as in the case of dormant Syphilis where infection can recur years after treatment.

The second consideration of treatment is to at least make a minimal assessment of brain involvement in Lyme patients by evaluating the patient's neurocognitive symptoms and neurological responses.

If a Lyme patient has complained of having increased pressure in the head, or has an increased opening pressure on spinal tap, elevated albumin, or clinical signs of meningitis then it is vital to treat them as though they have an infection of the brain and not to make matters worse by capriciously treating with high dose antibiotics without thought to increasing cerebral edema and inflammation. A spinal tap may be unrevealing and aseptic in many of these patients, but the clinical picture of brain involvement should not be ignored.

These patients potentially can be made worse when active infection is attacked and killed within the brain. The bacterial by products are immunogenic and can stimulate the immune system to cause a very site-specific inflammation. In work reviewed by:

Tuomanen Elaine. Breaching the Blood Brain Barrier: Development of a therapy for meningitis has revealed how bacteria penetrate the Blood-brain barrier. Scientific American February 1993 pp 80-85

It was found that without pretreating the brain for potential inflammation when treating pneumococcal meningitis in infants, that you would have an overall mortality rate of greater than 30 %. But by pretreating with a powerful nonsteroidal anti-inflammatory that affects leukotrienes and prostaglandins, and a ten day course of steroids along with the penicillin, it reduced the overall mortality to about 8 % .

(One NSAID that blocks leukotrienes is ketoprofen or Orudis, but in the Viox aftermath it has become hard to find.)

The goal in treating Lyme disease would not be to decrease mortality, but to decrease morbidity of neurocascade events caused by rapid brain cell trauma from a rapid rise in inflammatory cytokines. In other words doing a pre-emptive strike against a Herxheimer-like reaction in the brain.

The thought of steroids in Lyme seems shocking to some, but used for a few days they can offer a reduction in morbidity to those with intracranial pressure from Lyme encephalitis. The caveat is to treat long past the ten days of steroids with further antibiotics to assure eradication of Borrelia from the CNS.

The third and final consideration in treating Lyme encephalopathy lies in the neurochemistry of the brain during a neurocascade event.

In a concussion it is the rapid release of glutamate that causes the overstimulation of the N-methyl D-asparate receptor on the brain neuron membrane. In Lyme it is the over production of quinolinic acid and the release of glutamate that overstimulates the NMDA receptor. The net result is that neurons rapidly and repeatedly fire and they become clogged with calcium, and become ineffective.

A neuron that is overstimulated past threshold repeatedly demyelinates, and can then interrupt other neurons in the neural complex. Without dendritic branching functioning properly we lose the ability to maintain complex neural networks. In short we simplify the brain and our ability to reason: our cognitive abilities as we see in the rat model would decrease.

Try to imagine your brain cells as being telephone lines transmitting information. If all of the telephone lines are busy you neither get information into or out of that area of the brain being affected.

So what can be done to minimize NMDA receptor overstimulation during antibiotic therapy or acute episodes of bacterial induced encephalopathy?

We know of two common OTC products that interfere with NMDA receptors. One is large doses of magnesium. Magnesium compete for the site causing agents like glutamate and quinolinic acid to be displaced. The effect is generally mild without side effects and may help Lyme patients remain more cognitive and alert. Magnesium IV is still given to avert NMDA triggered seizures during eclampsia. As much as 4 grams of magnesium sulfate is given by IV push.

The second agent to block NMDA receptors is the common OTC cough suppressant dextropromorphan or DM. Dextropromorphan binds to the NMDA receptor but does not have the same effect as the neurotoxins that over stimulate the NMDA receptor.

In low doses it appears to have a similar but more pronounced affect as magnesium and some Lyme patients with neurocognitive deficits report after a single oral dose of 30-60 mgs that they have an improvement of mental clarity, energy and ability to multi-task. Since these are only anecdotal accounts, we cannot draw any conclusions as to safety or efficacy until blinded studies are completed.

Unfortuantely dextropromorphan like many OTC medications has a history of being abused. Dextropromorthan is nonaddicting but in high single doses of 600-1,200 mgs can cause a hallucinogenic euphoria-like state, and at these dosages has been observed to cause some measurable brain changes and brain damage.

It would be a shame if such a simple treatment modality that has been safe and effective at OTC doses for 40 years would be withdrawn from the market just when it may prove to be useful in the treatment of Lyme and potentially other NMDA mediated diseases such as Multiple Sclerosis and Parkinson's disease where NMDA receptors are also over stimulated.

It is conceivable that dextropromorphan taken immediately after a brain injury or boxing match could have a slight amelioration affect of brain trauma by blocking the effects of glutamate flooding the NMDA receptors immediately after a brain trauma? I am sorry to say that I could find no studies to reference this possible usage of dextromethorphan.

Dextropromorphan also has a pronounced anesthetic effect at high doses similar to the related drug Ketomin/ketomine. It's role as a treatment modality for Lyme, MS, and sports injuries has not yet been evaluated, but in theory host-receptor blocking offers some hope in the direction that new therapies could take in years to come.

Tom Grier

Are you looking at the Dextropromorphan because it is OTC and easier to administer? It would be wonderful if something could be found to ameliorate this issue.

How much magnesium would have to be taken orally for benefit?

Something else you might be interested in is the use of low dose Dilantin (Phenytoin) as described in the book, "A Remarkable Medicine Has Been Overlooked," by Jack Dreyfuss.

Phenytoin stabilizes the bioelectrical activity of the cell membrane.
It relieves irritability, flash anger, headache, muscle twitches, etc, and helps one to concentrate and focus.

I bought the book used at Amazon.com, and was amazed. So many of the symptoms that this medication relieves are exactly the symptoms that Lyme patients have! I wonder why the LLMD's don't use low dose Dilantin to ease the suffering of their patients?

The answer probably is because they don't know about it. The drug is old, and the patent has run out, so there is no financial incentive for the company that owns it to market it.

I used pharmeceutical grade (powder) magnesium and calcium during the no-abx breaks during Lyme abx therapy.

I know that it's difficult for the body to absorb more than about 500 mg at one time (and I take the oxide- which about 59% elemental magnesium) and the status of calcium is important. When you reach bowel intolerance, you know it.

Experiementing on my self, I found that if I took 600mg Calcium/300 mg Magnesium 3 times per day, I didn't get diarreah, so I assumed I was absorbing as much as possible.

I agree with all the beneficial effects mentioned in Ton's article about it (and GiGi's previous ones).

Re: "there must be a receptor" that is my goal now to find the receptor.

Re: MMP's, I recently met Trent Nichols MD a mostly alternative doc in PA, he and wife have lyme. He has done abx and mepron etc, but it was not sufficient. He's pretty active and healthy as far as I can see, but anyway, one product that helped him a lot he said is comitras from natcell/atrium biotech. It downregulates MMP's which are elevated in about 3/4 lymies. I'm going to try it. However this is not a universal solution as the cost is very high.

I have begun thinking recently in a similar direction as the above article although with slightly different emphasis. You certainly could downregulate virulence and various cascades and I know I've done that intuitively with some of the things I've used, finding the rationale for them later on. To continue to do that is a good idea as you minimize longterm damage. However, I also have been inspired by other unrelated research I've seen on bugs and various sugar receptors. The macrophage has 4 mannose receptors. A recent study I saw found that 3 strains of lactobacilli are mannose loving and will latch onto the mannose on the surface of HIV in its presence, thereby neutralizing it. I have become curious about exactly what receptor(s) BB uses to initially adhere and what the inflammatory cascade is. I know lipoproteins are involved but I would also like to know what sugars are involved. Not that others aren't thinking this way, there is a researcher, Griffiths, in Australia who has synthesized carbohydrates and hopes to eventually use them as drugs.

Mild brain fog and malaise seem to make up a large chunk of the neuro-Lyme continuum, but there are other presumably less common manifestations that are a good bit more extreme.

I'm wondering how more extreme presentations may be reflected at the level of these nerve receptors.

By "extreme presentations" I mean things like:

Long fits of shaking so violently that a friend who's very strong can't hold my body still;

Internal vibrations like a tuning fork that has been slammed against a hard surface, but instead of disippating build in intensity until it's like having your insides in a paint-shaker;

"Earthquakes" - they feel exactly like a real, strong, quake (I was at the epicenter of Loma Prieta in '89);

White-outs, black-outs, flicker, vignetting and other sustained interruptions of normal vision;

Loss not only of peripheral motor control but normal speech, and stroke-like inability to pronounce certain sounds (can linger for several hours after a fit);

What feels like a rapid alternation of various 'almost but not quite passing out' states.

Each of these symptoms occur independently, but there are long fits when they all strike at once, in a sequence that varies in some respects but always seems to hit a peak or crescendo and then trail off almost as abruptly as they hit, followed by intense fatigue and disorientation.

Any clue what we might see at the level of nerve receptors in these chaotic states, and how that is different from what we see when presentation is pretty well confined to brain fog and fatigue?

What is your medical background? If you are a dr. or whatever, would you edit what you show here at the top adding your medical profession and date/year written?

From what I read, I think your article would be helpful to our LLMDs and/or possibly to the SS disability admin law judges determining if we are disabled or not. I've been trying to get SSDI benefits for 5 yrs. in 8-05!

Thanks Tom for considering my suggestion.

I guess you mean DEXTROMETHORPHAN?

Nelly

second agent to block NMDA receptors is the common OTC cough suppressant dextropromorphan or DM. Dextropromorphan binds to the NMDA receptor but does not have the same effect as the neurotoxins that over stimulate the NMDA receptor.

Unless I had great insurance I would not bother with such tests as my symptoms are good enough .

Paul...sorry you are still having such trouble. I hope you are trying IV magnesium, glutathione (btw------a lymie I know in Colorado who has a mild hbo chamber, also recently started using glutathoine via a nebulizer and it is healing her lungs and giving her a lot of enregy. The nebulizer is called Inspiration and I saw it on the web for about $60 as the best price. The glutathione can be obtained from Wellness Pharmacy via rX. This treatment should not be too expensive and certainly cheaper than IV and can be done at home). I also hope you will get a chance to try hbo some way or other. I happen to be down in Atlanta for a few days on a mixture of health reasons, see one of my best friends, and a bit of business. Anyway, I not suprrisingly had a mild lymegraine after the flight and got into the chamber at the clinic.

It did help but not totally, because they were only running 5 liters a minute concentrator. Also, it just happened to be the mid sized chamber, I've never been in any but the big size. Sorry this is off topic, but it worked fine but I really like the big ones much better.

Anyway...I do think magnesium IV or IM would help you. Cheney recommends IM with taurine so it wont cause a cyst. I remember you can't take gaba drugs.

Also I forgot to mention, via Tom's post, that I also seem to have a craving for potassium. I get it from biotech--pure powder. I will just eat 1/4 teaspoon and it actually tastes GOOD to me. I find it also helps me sleep better. So it is always interesting to mewhen Ifind that the supplements I crave (say, magnesium and potassium) have a rationale...whereas the supplements I avoid (calcium), there is a rationale for that...

Need to print this out to see if I can make sense of it later.

From my Updated Nutshell post:

CoQ10 Deficiency caused by lack of other vitamins (like Vitamin B6) the body needs to manufacture CoQ10. If CoQ10 is deficient, nerve cells in the brain and elsewhere may not have the ability to withstand the overstimulation caused by excess glutamate.
http://www.msgtruth.org/why.htm.

And this today:

When a neurotransmitter called Acetylcholine is released from one neuron, it binds to Acetylcholine receptors on the neighbouring neuron. Consequently, the receptor is `unlocked' and a `door' into a neuron is now open.

Sodium (Na+) ions enter and potassium (K+) ions leave the neuron through this opening. This movement of ions generates an electric signal in the neuron. When this happens we say that the neuron is `excited'. Neurons that are `unlocked' by Acetylcholine are involved in muscle contraction, wakefulness, attentiveness, sexuality, and thirst, among other things.

All neurotransmitters, including Acetylcholine, have a `use-by' date. This means that after `unlocking' a neuron for a short period of time neurotransmitters are removed, degraded or recycled. For example, Acetylcholine is cut up and deactivated by a specialised protein called Acetylcholine Esterase.

Glutamate is an important neurotransmitter that causes excitation of neurons and is involved in learning and memory. Glutamate can `unlock' two different types of receptors and expose neurons to two different types of chemical messages. One of these receptors, called NMDA receptor, is very important in the learning and memory processes.

`Locked' NMDA receptor is also `guarded' by magnesium (Mg+) ions which sit on top of the receptor and prevent glutamate from unlocking it. Only under very specific conditions glutamate can displace magnesium ions and unlock the receptor. When this happens calcium (Ca+) ions enter the neuron and generate an electric signal. This type of signal is very important for learning process.

Brains affected by Alzheimer's disease undergo many changes some of which may cause NMDA receptors to malfunction. In a healthy brain NMDA receptors are tightly controlled and guarded, but in a brain affected by Alzheimer's disease these receptors are almost always 'unlocked'. As a result neurons are continually in an excited state and can no longer detect subtle chemical messages. In other words, there is too much background noise for neurons to detect real signals.
http://www.alzheimers.org.au/content.cfm?infopageid=1923

P.S. The neurotransmitter acetylcholine takes a big hit...thus there goes REM sleep down the tubes.
Dopamine drops. Serotonin goes up too much at first...develop antiserotonin antibodies...to help "conserve" dopamine???

"statin drugs as well as magnesium inactivate the enzyme 5-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase"

Now...Acetyl CoA links glycolysis and the Krebs cycle.

Genomic Sequence of Borrelia Burgdorferi...

Catalytic activity: ATP + Acetate = APD + acetyl phosphate

Pathway: Conversion of acetate to acetyl - CoA; first step.

In the cell wall is acetokinase.

The aminoglycosides are too tough...I know from personal experience. Vancomycin put my dad in toxic hepatitis and destroyed his one good remaining kidney.

Gotta go the safest route.