30-05-2013, 12:56 PM
Tetracyclines - Structure and Pharmacology
[attachment=54489]
Physical Properties
Highly functionalized, partially reduced naphthacene (4 linearly fused 6-membered rings)
Has three pK values:
2.8 – 3.4
7.2 – 7.8
9.1 – 9.7
Iso-electric point at pH 5
Commercially available as water – soluble hydro chloride salts
Phototoxicity
Recognition of drug degradation products by target proteins: isotetracycline binding to Tet repressor.
Gesa Volkers, Lothar Petruschka, and Winfried Hinrichs J Med Chem 54(14):5108-15 (2011), PMID 21699184
Tetracycline antibiotics and their degradation products appear in medically treated tissues, food, soil, and manure sludge in the environment. In the context of protein interactions with various tetracyclines we performed crystal structure analyses of the tetracycline repressor in complex with weak or noninducing tetracycline derivatives. Isotetracyclines are degradation products of tetracyclines, which occur under physiological conditions. The typical framework of the antibiotic is irreversibly broken at the BC-ring connection, leading to a modified orientation of the AB to the new C*D ring fragments.
The shape of the zwitterionic AB-ring fragment is unchanged and still binds to the TetR recognition site in a manner comparable to the intact antibiotic but without typical Mg(2+) chelation. This work is an example that drug degradation products can still bind to specific targets and should be discussed in light of potential and critical side effects.
Other Modes of Action
More lipophilic tetracyclines
like Minocycline disrupt
membrane function
Enter bacteria through porin
routes through outer
membrane by forming highly
lipophilic Ca and Mg chelates
Depper passage through inner
cytoplasmic membrane requires
energy. Suggests that bacteria mistakes
Tetracyclines to be food!
Resistance
Unusual ribosomal protection process by bacterial proteins: TET(M), TET(O), TET(Q).
Allows protein biosynthesis to continue in the presence of bound Tetracyclines.
Efflux of Mg - chelated Tetracyclines in exchange of protons (Prominent in Gram –ve cells).
Some microbes such as Mycoplasma and Neisseria have modified enzymes that accumulate fewer Tetracyclines because of defective passage through porins.
Imperfect distinction between bacteria 70S ribosomes and mammalian 80S Ribosomes; in high doses or during intravenous use in pregnancy, they demonstrate a significant anabolic effect – Leads to sever liver and kidney damage.
Antimicrobial Spectra
Wide bacteriostatic activity; but, resistance and comparative frequency of side – effects make them unpopular.
Difference between spectra of various Tetracyclines is not large.
Popular for low – dose treatment of acne, urinary tract infections (due to E.coli), upper respiratory tract infections, ophthalmic infections, cholera etc.
In Agriculture, as feed supplements where animals reach market weight more quickly and economically with their use.
[attachment=54489]
Physical Properties
Highly functionalized, partially reduced naphthacene (4 linearly fused 6-membered rings)
Has three pK values:
2.8 – 3.4
7.2 – 7.8
9.1 – 9.7
Iso-electric point at pH 5
Commercially available as water – soluble hydro chloride salts
Phototoxicity
Recognition of drug degradation products by target proteins: isotetracycline binding to Tet repressor.
Gesa Volkers, Lothar Petruschka, and Winfried Hinrichs J Med Chem 54(14):5108-15 (2011), PMID 21699184
Tetracycline antibiotics and their degradation products appear in medically treated tissues, food, soil, and manure sludge in the environment. In the context of protein interactions with various tetracyclines we performed crystal structure analyses of the tetracycline repressor in complex with weak or noninducing tetracycline derivatives. Isotetracyclines are degradation products of tetracyclines, which occur under physiological conditions. The typical framework of the antibiotic is irreversibly broken at the BC-ring connection, leading to a modified orientation of the AB to the new C*D ring fragments.
The shape of the zwitterionic AB-ring fragment is unchanged and still binds to the TetR recognition site in a manner comparable to the intact antibiotic but without typical Mg(2+) chelation. This work is an example that drug degradation products can still bind to specific targets and should be discussed in light of potential and critical side effects.
Other Modes of Action
More lipophilic tetracyclines
like Minocycline disrupt
membrane function
Enter bacteria through porin
routes through outer
membrane by forming highly
lipophilic Ca and Mg chelates
Depper passage through inner
cytoplasmic membrane requires
energy. Suggests that bacteria mistakes
Tetracyclines to be food!
Resistance
Unusual ribosomal protection process by bacterial proteins: TET(M), TET(O), TET(Q).
Allows protein biosynthesis to continue in the presence of bound Tetracyclines.
Efflux of Mg - chelated Tetracyclines in exchange of protons (Prominent in Gram –ve cells).
Some microbes such as Mycoplasma and Neisseria have modified enzymes that accumulate fewer Tetracyclines because of defective passage through porins.
Imperfect distinction between bacteria 70S ribosomes and mammalian 80S Ribosomes; in high doses or during intravenous use in pregnancy, they demonstrate a significant anabolic effect – Leads to sever liver and kidney damage.
Antimicrobial Spectra
Wide bacteriostatic activity; but, resistance and comparative frequency of side – effects make them unpopular.
Difference between spectra of various Tetracyclines is not large.
Popular for low – dose treatment of acne, urinary tract infections (due to E.coli), upper respiratory tract infections, ophthalmic infections, cholera etc.
In Agriculture, as feed supplements where animals reach market weight more quickly and economically with their use.