Tetracycline antibiotics
[1] Tetracycline molecules comprise a linear fused tetracyclic nucleus (rings designated A, B, C and D) to which a variety of functional groups are attached.
These modifications do not change their broad antibacterial activity, but do affect pharmacological properties such as half-life and binding to proteins in serum.
[1] Tetracyclines were discovered in the 1940s and exhibited activity against a wide range of microorganisms including gram-positive and gram-negative bacteria, chlamydiota, mycoplasmatota, rickettsiae, and protozoan parasites.
[2] Tetracyclines are growth inhibitors (bacteriostatic) rather than killers of the infectious agent (bacteriocidal) and are only effective against multiplying microorganisms.
The widespread use of tetracyclines is thought to have contributed to an increase in the number of tetracycline-resistant organisms, in turn rendering certain infections more resilient to treatment.
[9] Doxycycline is also used as a prophylactic treatment for infection by Bacillus anthracis (anthrax) and is effective against Yersinia pestis, the infectious agent of bubonic plague.
The breakdown products of tetracyclines are toxic and can cause Fanconi syndrome, a potentially fatal disease affecting proximal tubular function in the nephrons of the kidney.
Despite these studies, many physicians still recommend the use of barrier contraception for people taking any tetracyclines to prevent unwanted pregnancy.
This mechanism does not add to their antibiotic effects, but has led to extensive research on chemically modified tetracyclines or CMTs (like incyclinide) for the treatment of rosacea, acne, diabetes and various types of neoplasms.
[24][25][26] It has been shown that tetracyclines are not only active against broad spectrum of bacteria, but also against viruses, protozoa that lack mitochondria and some noninfectious conditions.
The binding of tetracyclines to cellular dsRNA (double stranded RNA) may be an explanation for their wide range of effect.
[27] Several trials have examined modified and unmodified tetracyclines for the treatment of human cancers; of those, very promising results were achieved with CMT-3 for patients with Kaposi Sarcoma.
[30][29] Replacement of the carboxylamine group at C2 results in reduced antibacterial activity but it is possible to add substituents to the amide nitrogen to get more soluble analogs like the prodrug lymecycline.
[2] The simplest tetracycline with measurable antibacterial activity is 6-deoxy-6-demethyltetracycline and its structure is often considered to be the minimum pharmacophore for the tetracycle class of antibiotics.
This is partly because most tetracyclines bind with food and also easily with magnesium, aluminium, iron and calcium, which reduces their ability to be completely absorbed by the body.
[39] The history of the tetracyclines involves the collective contributions of thousands of dedicated researchers, scientists, clinicians, and business executives.
[2][40] Chlortetracycline (Aureomycin) was first discovered as an ordinary item in 1945 and initially endorsed in 1948[41] by Benjamin Minge Duggar, a 73-year-old emeritus professor of botany employed by American Cyanamid – Lederle Laboratories, under the leadership of Yellapragada Subbarow.
Duggar derived the substance from a Missouri soil sample, golden-colored, fungus-like, soil-dwelling bacterium named Streptomyces aureofaciens.
But ultimately oxytetracycline (terramycin) was isolated in 1949 by Alexander Finlay from a soil sample collected on the grounds of a factory in Terre Haute, Indiana.
Pfizer advertised the drug heavily in medical journals, eventually spending twice as much on marketing as it did to discover and develop terramycin.
[43] The Pfizer group, led by Francis A. Hochstein, in loose collaboration with and Robert Burns Woodward, determined the structure of oxytetracycline, enabling Lloyd H. Conover to successfully produce tetracycline itself as a synthetic product.
Within a few years, a number of semisynthetic tetracyclines had entered the market, and now most antibiotic discoveries are of novel active derivatives of older compounds.
[47] Tetracyclines were noted for their broad spectrum antibacterial activity and were commercialized with clinical success beginning in the late 1940s to the early 1950s.
The second-generation semisynthetic analogs and more recent third-generation compounds show the continued evolution of the tetracycline platform towards derivatives with increased potency as well as efficacy against tetracycline-resistant bacteria, with improved pharmacokinetic and chemical properties.
[51] Although it is structurally related to minocycline, alterations to the molecule resulted in its expanded spectrum of activity and decreased susceptibility to the development of resistance when compared with other tetracycline antibiotics.
