Tetracyclines: Tetracycline, Oxytetracycline, Chlortetracycline, Minocycline, Doxycycline

1. TETRACYCLINES

2. Introduction
Tetracyclines are a group of broad-spectrum antibiotic compounds that have a common basic
structure and are either isolated directly from several species of Streptomyces or produced
semi-synthetically from those isolated compounds. Tetracycline molecules comprise a linear
fused tetracyclic nucleus (rings designated A, B, C and D) to which a variety of functional
groups are attached.

3. Tetracyclines are named for their four (tetra-) rings (-cycl-) derivation (-ine). They are defined
as a subclass of polyketides, having an octahydrotetracene-2-carboxamide skeleton and are
known as derivatives of polycyclic naphthacene carboxamide.
Tetracycline

4. While all tetracyclines have a common structure, they differ from each other by the presence
of chloride, methyl, and hydroxyl groups. These modifications do not change their broad
antibacterial activity, but do affect pharmacological properties such as half-life and binding to
proteins in serum.
Tetracyclines were discovered in the 1940s and exhibited activity against a wide range of
microorganisms including gram-positive and gram -ve bacteria, chlamydiae, mycoplasmas,
rickettsiae and protozoan parasites. Tetracycline itself was discovered later than
chlortetracycline and oxytetracycline but is still considered as the parent compound for
nomenclature purposes.

5. The history of the tetracyclines involves the collective contributions of thousands of dedicated
researchers, scientists, clinicians, and business executives.
Tetracyclines were discovered in the 1940s, first reported in scientific literature in 1948, and
exhibited activity against a wide range of microorganisms.
The first members of the tetracycline group to be described were chlortetracycline and
oxytetracycline. Chlortetracycline (Aureomycin) was first discovered as an ordinary item in
1945 and initially endorsed in 1948 by Benjamin Minge Duggar, a 73-year-old emeritus
professor of botany employed by American Cyanamid – Lederle Laboratories, under the
leadership of Yellapragada Subbarow.

7. Duggar derived the substance from a Missouri soil sample, golden-colored, fungus-like, soil-
dwelling bacterium named Streptomyces aureofaciens. About the same time as Lederle
discovered aureomycin.
Oxytetracycline (terramycin) was isolated in 1949 by Alexander Finlay from a soil sample
collected on the grounds of a factory in Terre Haute, Indiana. It came from a similar soil
bacterium named Streptomyces rimosus.
From the beginning, terramycin was a molecule enveloped in controversy. It was the subject
of the first mass-marketing campaign by a modern pharmaceutical company. Pfizer advertised
the drug heavily in medical journals, eventually spending twice as much on marketing as it did
to discover and develop terramycin.

8. Still, it turned Pfizer, then a small company, into a pharmaceutical giant. 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.
In 1955, Conover discovered that hydrogenolysis of aureomycin gives a deschloro product that
is just as active as the original product. This proved for the first time that chemically modified
antibiotics could have biological activity. 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.

9. Other tetracyclines were identified later, either as naturally occurring molecules, e.g.,
tetracycline from S. aureofaciens, S. rimosus, and S. viridofaciens and dimethyl-
chlortetracycline from S. aureofaciens, or as products of semisynthetic approaches, e.g.,
methacycline, doxycycline, and minocycline.
Glycylcyclines and fluorocyclines are new classes of antibiotics derived from tetracycline.
These tetracycline analogues are specifically designed to overcome two common mechanisms
of tetracycline resistance, namely resistance mediated by acquired efflux pumps and/or
ribosomal protection.

10. In 2005, tigecycline, the first member of a new subgroup of tetracyclines named
glycylcyclines, was introduced to treat infections that are resistant to the other antimicrobial
agents.
Eravacycline (formerly known as TP-434) received FDA approval on Aug 27, 2018 for
treatment of complicated intra-abdominal infections.
Sarecycline (formerly known as WC 3035) received FDA approval on Oct 1, 2018 for
treatment of moderate to severe acne vulgaris.
Omadacycline (formerly known as PTK-0796) received FDA approval on Oct 2, 2018 for
treatment of community-acquired pneumonia and acute skin and skin structure infections.

11. Classification

12. Antibiotic Source Half-life Structure
Tetracycline
Naturally
occurring
6–8 hours (short)
Chlortetracycline
Naturally
occurring
6–8 hours (short)
Oxytetracycline
Naturally
occurring
6–8 hours (short)

13. Antibiotic Source Half-life Structure
Demeclocycline
Naturally
occurring
12 hours
(intermediate)
Lymecycline Semi-synthetic 6–8 hours (short)
Meclocycline Semi-synthetic 6–8 hours (short)

14. Antibiotic Source Half-life Structure
Methacycline Semi-synthetic
12 hours
(intermediate)
Minocycline Semi-synthetic 16+ hours (long)
Rolitetracycline Semi-synthetic 6–8 hours (short)

15. Antibiotic Source Half-life Structure
Doxycycline Semi-synthetic 16+ hours (long)
Tigecycline Glycecyclines 16+ hours (long)
Eravacycline Newer 16+ hours (long)

16. Antibiotic Source Half-life Structure
Sarecycline Newer 16+ hours (long)
Omadacycline Newer 16+ hours (long)

17. Mechanism of action
Tetracycline antibiotics are protein synthesis inhibitors. They inhibit the initiation of
translation in variety of ways by binding to the 30S ribosomal subunit, which is made up of
16S rRNA and 21 proteins. They inhibit the binding of aminoacyl-tRNA to the mRNA
translation complex. Some studies have shown that tetracyclines may bind to both 16S and
23S rRNAs.

19. Video:
https://www.youtube.com/watch?v=ifdv-G2cmwA
https://www.youtube.com/watch?v=Zfoa4BzjClM

20. Therapeutic uses
Tetracyclines are generally used in the treatment of infections of the urinary tract, respiratory
tract, and the intestines and are also used in the treatment of chlamydia, especially in patients
allergic to β-lactams and macrolides.
Tetracyclines are widely used in the treatment of moderately severe acne and rosacea
(tetracycline, oxytetracycline, doxycycline or minocycline).

21. Anaerobic bacteria are not as susceptible to tetracyclines as are aerobic bacteria. 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.
They are also used in veterinary medicine. They may have a role in reducing the duration and
severity of cholera, although drug-resistance is mounting and their effect on overall mortality
is questioned.

22. Doxycycline is also used for malaria treatment and prophylaxis, as well as treating elephantitis
filariasis. Tetracyclines remain the treatment of choice for infections caused by chlamydia
(trachoma, psittacosis, salpingitis, urethritis and L. venereum infection), Rickettsia (typhus,
Rocky Mountain spotted fever), brucellosis and spirochetal infections (borreliosis, syphilis and
Lyme disease).

23. SAR

25. Antibiotic and non-antibiotic characteristics of tetracyclines may be reduced by modifying the
lower peripheral zone; on the other hand, modification in the upper peripheral zone enhanced
the attack on biological targets, particularly at positions C7 through C9 of the D ring. This has
been lead toward the formation of semi-synthetic compounds such as minocycline and
doxycycline.
Minocycline Doxycycline

26. The presence of an amino group in position C4 and ketoenolic tautomers in position C1 and
C3 of the A ring is necessary for tetracycline to take action as inhibitor of protein synthesis.
The presence of the amino group in the C4 position is vital for antibiotic activities.
Antibacterial activity against Gram-negative bacteria may be decreased by epimerization of
natural 4S isomer of C4-dimethlyamino group to its 4R isomer. It also requires a C10-phenol
and C11-C12 keto-enol substructure in conjunction with a 12a-OH group in the lower
peripheral region.

27. Modification of R1, R2, R3 groups gives better selectivity to the biological target in antifungal
but not for antibacterial activity.
The D-ring is most flexible to change by showing antibacterial activity. All modifications of
R4, R5 and R6 groups are required to give highly bacterial specificity and deep changing in
pharmacokinetics.
An active tetracycline requires a C10 phenol as well as a C11-C12 keto-enol substructure in
conjugation with a 12a-OH group and a C1-C3 diketo substructure.
Removal of the dimethylamine group at C4 reduces antibacterial activity of the tetracycline
antibiotics.

28. 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.
Lymecycline

29. 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 tetracycline class of antibiotics.
C5-C9 can be modified to design various tetracycline derivatives with varying antibacterial
activity.

30. Chemical Degradation
When ingested, it is usually recommended that the more water-soluble, short-acting
tetracyclines (plain tetracycline, chlortetracycline, oxytetracycline, demeclocycline and
methacycline) be taken with a full glass of water, either two hours after eating or two hours
before eating. 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.
Dairy products, antacids and preparations containing iron should be avoided near the time of
taking the drug. Partial exceptions to these rules occur for doxycycline and minocycline,
which may be taken with food (though not iron, antacids, or calcium supplements).

34. Thank You