Table of Contents

Science behind Marshall Protocol antibiotics

NOTE: Antibiotics are no longer considered a part of the Marshall ProtocolA curative medical treatment for chronic inflammatory disease. Based on the Marshall Pathogenesis..

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Safety of Marshall Protocol antibiotics

Pulsed low-dosing of Marshall Protocol antibiotics

Bactericidal vs. bacteriostatic antibiotics

As a whole, the antibiotics employed by the Marshall Protocol have a primarily bacteriostatic as opposed to a bactericidal action. Bactericidal antibiotics kill the bacteria causing the infection through direct action, usually by causing the cells to split open, or lyse. Bacteriostatic antibiotics act on the internal workings of the bacterial cell to stop it dividing, decreasing the production of bacterial exoproteins, and so slow down the advance of the infection.

Generally speaking, bacteriostatic antibiotics place the burden for clearing an infection on an active immune response.

Mechanisms of action

Emerging research now suggests that antibiotics have much broader range of actions that once supposed.

Name Action(s)
Minocycline interferes with bacterial protein synthesis by binding to the 30S subunit of the bacterial ribosome; may bind the PXR Nuclear ReceptorIntracellular receptor proteins that bind to hydrophobic signal molecules (such as steroid and thyroid hormones) or intracellular metabolites and are thus activated to bind to specific DNA sequences which affects transcription.; inhibits activity of caspase-3
Azithromycin (Zithromax) no longer recommended interferes with bacterial protein synthesis by binding to the 50S subunit of the bacterial ribosome; significantly inhibited expression of co-stimulatory molecules (CD40 and CD86) and major histocompatibility complex (MHC) class II by dendritic cells; reduces toll-like receptor 4 expression, interleukin-12 production and the allostimulatory capacity of dendritic cells1)
Clindamycin interferes with bacterial protein synthesis by binding to the 50S subunit of the bacterial ribosome
Demeclocycline (Declomycin) interferes with bacterial protein synthesis by binding to the 30S and 50S subunit of the bacterial ribosome
Bactrim DS inhibits dihydropteroate synthase, an enzyme that allows bacteria to use folic acid

Inhibition of bacterial ribosome activity (minocycline, clindamycin, demeclocycline)

All the MP antibiotics except Bactrim are bacteriostatic. Bacteriostatic antibiotics are a class of antibiotics that work by disabling bacterial ribosomes – small, dense, structures that allow the pathogens to replicate and survive. When an antibiotic binds to a bacterial ribosome, it limits the growth of bacteria by interfering with bacterial protein production, DNA replication, or other aspects of bacterial cellular metabolism.

Folate reductase inhibition (Bactrim DS)

Bactrim DS works by interfering with the ability of bacteria to create and replicate their DNA. Bactrim DS inhibits dihydropteroate synthase, an enzyme that allows bacteria to use folic acid. Since folic acid is an essential precursor in the synthesis of several of the base pairs needed to create DNA, inhibition of the enzyme will stop the pathogen from creating the genetic material it needs to survive.

Activation of Pregnane X Nuclear Receptor (minocycline)

The affinity (Kd) of minocycline for the bacteria's 30S ribosome is not as high as one might otherwise expect based on its action. For this reason, it seems likely that minocycline may affect immune function in other ways. One possibility is the Pregnane X Nuclear Receptor (PXR).

A recent paper has suggested that various tetracycline antibiotics including clindamycin activate the PXR.2) Whether that conclusion is confirmed by further research remains to be seen.

The conclusion of that paper is somewhat at odds with the in silicoExperiment technique performed on computer or via computer emulation. model produced by Trevor Marshall, PhD, from which he has concluded that of the tetracyclines, minocycline is the only one that activates the PXR.

If this were true, the activation of the PXR by minocycline would confirm patient reports that suggest that taking extra minocycline provides symptom relief. When active, the PXR transcribes CYP3A4, which breaks down 1,25-DPrimary biologically active vitamin D hormone. Activates the vitamin D nuclear receptor. Produced by hydroxylation of 25-D. Also known as 1,25-dihydroxycholecalciferol, 1,25-hydroxyvitamin D and calcitirol., a vitamin D metabolite which interferes with the activity of the body's other nuclear receptorsIntracellular receptor proteins that bind to hydrophobic signal molecules (such as steroid and thyroid hormones) or intracellular metabolites and are thus activated to bind to specific DNA sequences which affect transcription..

Minocycline acting as a PXR agonist may be responsible for the palliation achieved when using high-dose minocycline, a treatment advocated by the Road Back Foundation.

Inhibition of caspase-3 (minocycline)

Caspase-3 is a protease, which breaks apart the VDRThe Vitamin D Receptor. A nuclear receptor located throughout the body that plays a key role in the innate immune response. receptor structure and thus limits the ability of VDR to do gene transcription. Minocycline is known to inhibit Caspase-3 activation.3)4)

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===== Notes and comments =====

===== References =====

1)
Iwamoto S, Kumamoto T, Azuma E, Hirayama M, Ito M, Amano K, Ido M, Komada Y. The effect of azithromycin on the maturation and function of murine bone marrow-derived dendritic cells. Clin Exp Immunol. 2011 Dec;166(3):385-92. doi: 10.1111/j.1365-2249.2011.04480.x.
[PMID: 22059997] [PMCID: 3232387] [DOI: 10.1111/j.1365-2249.2011.04480.x]
2)
Yasuda K, Ranade A, Venkataramanan R, Strom S, Chupka J, Ekins S, Schuetz E, Bachmann K. A comprehensive in vitro and in silico analysis of antibiotics that activate pregnane X receptor and induce CYP3A4 in liver and intestine. Drug Metab Dispos. 2008 Aug;36(8):1689-97. doi: 10.1124/dmd.108.020701. Epub 2008 May 27.
[PMID: 18505790] [PMCID: 4664062] [DOI: 10.1124/dmd.108.020701]
3)
Chang C, Cherng C, Liou W, Liao C. Minocycline partially inhibits caspase-3 activation and photoreceptor degeneration after photic injury. Ophthalmic Res. 2005 Jul-Aug;37(4):202-13. doi: 10.1159/000086610. Epub 2005 Jun 29.
[PMID: 15990464] [DOI: 10.1159/000086610]
4)
Festoff BW, Ameenuddin S, Arnold PM, Wong A, Santacruz KS, Citron BA. Minocycline neuroprotects, reduces microgliosis, and inhibits caspase protease expression early after spinal cord injury. J Neurochem. 2006 Jun;97(5):1314-26. doi: 10.1111/j.1471-4159.2006.03799.x. Epub 2006 Apr 21.
[PMID: 16638021] [DOI: 10.1111/j.1471-4159.2006.03799.x]