Megan weitner's 2016 thesis

Mechanisms of action

Membrane permeability or homeostasis mechanisms:

Hydroxychloroquine: As a base, it alters the intracellular pH by attracting acids. This may disurpt the ion transport gradient, preventing cells from acquiring the necessary nutrients in their dormant state. When combined with drugs that act on DNA transcription, activity from transmembrane proteins may also be affected, further preventing the cells from maintaining their necessary nutrient and ion balance.
Fluconazole: Fluconazole is an antifungal drug that inhibits cytochrome p-450-dependent 14α-sterol demethylase, resulting in an inhibition of ergosterol. While normally exclusive to fungal membranes, Borrelia utilize ergosterol in their membranes to maintain fluidity and membrane integrity. The membrane dysfunction caused by the addition of fluconazole could allow for increased cellular penetration of the other drugs, but it could also function through disruption of nutrition uptake.

Free radical producing:

Methylene blue: This photosensitive dye produces free radicals and hydroxides when exposed to light. These free radicals cause lipid peroxidation, resulting in the loss of membrane integrity, and possibly damage to the peptides in the bacterial cell wall. If methylene blue is able to penetrate the cell wall, the drug can bind to and modify guanine residues, though the effect of this on inhibition of DNA replication has not been determined.

Artemisinin: Once activated, artemisinin’s endoperoxide bridge causes the creation of reactive oxygen species which can be rearranged into carbon-centered radicals. Both species of free radicals accumulate in neutrally charged lipids and thiols resulting in lipid peroxidation. The free radicals can also cause damage to DNA and metabolic enzymes resulting in disruption of DNA transcription and cellular metabolism. Artemisinin has also been suggested to be involved in protein alkylation, resulting in inhibition of cysteine proteases.

Protein synthesis inhibitor:

Doxycycline:
Azithromycin:
Nitrofurantoin: Functions through the creation of free radicals and protein dysfunction. Nitrofurantoin must be activated through intracellular reduction, which results in the creation of electrophiles. These reactive species result in the inhibition of components of the citric acid cycle, along with causing damage to DNA, RNA and protein synthesis mechanisms.55 Nitrofurantoin also functions as a diamide and causes the creation of nonnative disulfide bonds in bacterial proteins, resulting in protein dysfunction.

DNA transcription: