Beyond Antibiotics: Tetracyclines' Diverse Uses

Tetracyclines are broad-spectrum antibiotics that interfere with protein synthesis.

Short history of tetracyclines

Tetracyclines were discovered in 1948 in the fermented products of soil bacteria Streptomyces aureofaciens. There are now three types of tetracycline available – tetracycline natural products, tetracycline semisynthetic compounds, and chemically modified tetracyclines (CMTs).

Dermatologists used them in the early 50s when it was found they could treat acne, however research has now branched into how tetracyclines can affect several other functions and pathways. (Inflammation, proteolysis (protein breakdown), angiogenesis (new blood vessel formation from other blood vessels), apoptosis (programmed cell death), metal chelation, ionophoresis (separating ions electrically), bone metabolism.)

The chemistry of tetracyclines

The basic (effective) chemical structure of tetracyclines and its analogues has a tetracyclic naphthacene carboxamide ring system. Those varities with antibiotic activity has a dimethylamine group at carbon 4 (C4) in ring A.

If you remove the dimethylamino group from C4, it reduces the antibiotic effect, but increases the nonantibiotic actions. This strategy has resulted in several chemically modified tetracyclines. Semisynthetic compounds of tetracycline are doxycycline and minocycline.

Tetracyclines for inflammation

Research has examined the anti-inflammatory properties of tetracyclines both in and out of the lab. Results range from reducing lymphocytic proliferation, suppressing neutrophilic migration and chemotaxis, to accelerating degradation of nitric oxide synthetase.

Tetracycline and analogues can inhibit collagenases and gelatinases involved in remodeling connective tissue, embryogenesis, wound healing, rheumatoid arthritis, and tumour invasion and metastasis.
Many diseases cause angiogenesis, including rosacea, some autoimmune conditions, and some cancers. Minocycline and doxycycline inhibit angiogenesis by implanted tumours in rabbit corneas. More research is needed.
Apoptosis (programmed cell death) was prevented in mice after a traumatic brain injury by inhibiting caspase-1. It reduced tissue injury and neurological deficits, decreased lesion size, and therefore may be useful clinically in Huntington disease and amyotrophic lateral sclerosis.
In a dog model, administration of doxycycline reduces the severity of canine osteoarthritis by increasing collagenase activity among other impacts. Minocycline stimulates new bone formation, prevents osteoporotic drops in bone density, which is clinically significant in postmenopausal women.

Tetracyclines for dermatological conditions

Clinical studies have been run on acne, rosacea, bullous dermatoses, sarcoidosis, Kaposi’s sarcoma, pyoderma gangrenosum, hidradenitis suppurativa, Sweet’s syndrome, alpha-1-antitrypsin deficiency panniculitis, and pityriasis lichenoides chronica.

Acne – down-regulate P acnes lipase, inhibit neutrophil chemotaxis, and inhibit proinflammatory cytokines and MMP-9. Can use tetracycline, minocycline and doxycycline.
Rosacea – inhibits angiogenesis, inhibits neutrophil chemotaxis, and inhibits proinflammatory cytokines and MMP-9. Can use tetracycline, minocycline and doxycycline.
Bullous dermatoses – inhibits MMP-2 and MMP9, inhibits neutrophil chemotaxis. Can use tetracycline and minocycline, with or without nicotinamide.
Cutaneous sarcoidosis – inhibits granuloma formation by inhibiting protein kinase C. Minocycline used.
Kaposi’s sarcoma – inhibits MMP-2 and angiogenesis. Can use tetracycline, minocycline and doxycycline.
Neutrophilic dermatoses – inhibits neutrophil chemotaxis. Can use tetracycline, minocycline and doxycycline.

Treating autoimmune disorders, cardiovascular and periodontitis with tetracyclines

Rheumatoid arthritis – minocycline reduces collagen-induced arthritis in rats and reduced the incidence of arthritis. In humans, there was improvements in joint tenderness, fewer swollen joints, and improvements in levels of C-reactive protein. Effects may be moderate.
Scleroderma – minocycline has demonstrated usefulness clinically with scleroderma patients – in an uncontrolled study of 11 people, 200mg daily was administered for a year in 11 patients with early diffuse scleroderma, and four of those 11 had their disease manifestation completely resolve.
Cancer – doxycycline, minocycline and CMTs may inhibit tumour growth by inhibiting MMPs and affecting cell proliferation.
Cardiovascular disease – doxycycline inhibits MMP-2 and MMP-9, so 200mg a week before aneurysm surgery showed a 3-fold reduction of aortic MMP-2 expression and a 4-fold reduction of MMP-9. This resulted in a significant reduction in aneurysm expansion rates. Doxycycline can also reduce some leukocyte activity in those with acute myocardial infarction.
Periodontitis – studies show that tetracycline, doxycycline and minocycline inhibit collagenase of gingival crevicular fluid taken from adult periodontitis. Significant improvements were made by 20mg of doxycycline twice daily on tooth attachment and pocket depth and bleeding after probing.

References

Sapadin, Allen N, Fleischmajer, Raul, Journal of the American Academy of Dermatology, Tetracyclines: Nonantibiotic properties and their clinical implications, February 2006, Volume 54, Issue 2, Pages 258–265