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Mauri Sergio Alves Palma
University of So Paulo
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*Correspondence: M. S. A. Palma. Departamento de Tecnologia Bioqumico-Farmacutica, Universidade de So Paulo. Av. Prof. Lineu Prestes, 580, Bloco
16, So Paulo-SP, Brasil. E-mail: msapalma@usp.br; aaborghi@usp.br
Review
Brazilian Journal of
Pharmaceutical Sciences
vol. 50, n. 1, jan./mar., 2014
http://dx.doi.org/10.1590/S1984-82502011000100003
26
A. A. Borghi, M. S. A. Palma
INTRODUCTION
HISTORIC OF TETRACYCLINE
27
APPLICATION
Tetracyclines in normal use concentrations are
FIGURE 1 - Relationship between the structure and activity of the molecule of tetracycline (Adapted from Pereira-Maia et al., 2010).
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A. A. Borghi, M. S. A. Palma
29
Bacteria
Gram-positive
Staphylococcus aureus (MS)
Staphylococcus aureus (MR)
Streptococcus pneumoniae (PS)
Streptococcus pneumoniae (PR)
Enteroccocus faecalis
Enteroccocus faecium
Gram-negative
Haemophilus influenza
Haemophilus influenza (BLP)
Klebsiella pneumoniae
Neisseria gonorrhoeae (PS, PR)
Escherichia coli
Atypical organisms
Chlamydia pneumoniae
Legionella pneumophila
Mycoplasma pneumoniae
ND = not determined
Tetracycline
Doxycycline
Minocycline
MIC90 (mg/L)
Tigecycline
1
32
32
64
128
64
0.5
2
8
8
16
16
0.12
2
8
16
32
16
0.5
0.5
0.125
0.125
0.25
0.25
0.5
1
4
>32
>8
3.1
ND
ND
2
ND
0.25
1
4
32
8
1
2
1
1
0.5
ND
1-8
1
0.25
4
1.6
ND
4
1
0.125
ND
0.25
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A. A. Borghi, M. S. A. Palma
COORDINATION OF METALS
Recently, several research groups have shown
that antibiotics containing metal complexes are often
more active than the parent compound. The coordination
platinum (II) to tetracycline and doxycycline through the
ring A, shown in Figure 1, results in active compounds
against bacterial strains resistant to tetracycline and other
antibiotics (Pereira-Maia et al., 2010; Rocha et al., 2011).
Some metal complexes are found in several articles
presented in the work by Pereira-Maia et al. (2010) and
are shown in Table II.
The palladium complex coordinated to tetracycline
is sixteen times more potent than the free drug. The
coordination of palladium to doxycycline also increases
the activity on resistant strains of bacteria, the complex
being two times more potent than the free drug (Rocha et
al., 2011). Table III shows the values of concentration of
each compound required to inhibit 50% of cell growth.
The coordination of antibiotic metal ions has been
used not only as a mechanism for reversing resistance, but
also as a strategy for developing new drugs, particularly
those with activity in the treatment of tumors, studies for
directing a new set of substances similar as the Chemically
Modified Tetracyclines known as CMTs. The removal
of the dimethylamino group in C11 position (Figure
1) eliminates the antibacterial action and potentiates
side effects. The chemotherapeutic action occurs
through inhibition of enzymes known as MMP (matrix
metalloprotease), focusing in prevention of angiogenesis
and metastasis (Pereira-Maia et al., 2010; Rocha et al.,
2011).
Despite several trials in developing these modified
molecules, their introduction in the market should be
carefully evaluated because the bioaccumulation of a
Solvent
pH
Product obtained
Coordination site
LnCl3 + TC.HCl
MeOH
7.0
[Ln(TC)Cl3].2H2O
O6, O7 e O15
MeOH
7.5
[Ni(TC)2(H2O)2]
Oxygens - ring A
MeOH
8.0
[Co(ATC)2(H2O)2]
Oxygens - ring A
K2PdCl4 + TC.HCl
H2O
NF
[Pd(TC)Cl2].2H2O
O12 e Oamide
K2PtCl4 + TC.HCl
H2O
NF
[Pt(TC)Cl2]
O12 e Oamide
* K2PtCl4 + 4.1 TC
Acetic acid
NF
[Pt(ATC)Cl2]
Ring A
H2O
NF
[Pt(DOX)Cl2].2H2O
O12 e Oamide
Toluen
NF
[Re(OTC)(CO)3Cl]
O 6 e O7
EtOH- Teof
NF
[Cu(TC)2(ClO4)2]
O12 e Oamide
EtOH- Teof
NF
[Fe(TC)2(ClO4)3]
O12 e Oamide
H2O- MeOH
NF
[Hg(OTC)Cl2].2H2O
O12 e Oamide
K2PtCl4 + DOX.HCl
* Re(CO)Cl + OTC.HCl
* Reaction made at 70 C. ** Reaction made between 40-50C. *** Crystals obtained at 8 C. Ln = Lanthanides in general,
Teof=Triethyl orthoformate, NF= pH not fixed. The coordination sites are shown in Figure 1.
IC50 (M)
Doxycycline
17.7
Tetracycline
52.37
34.54
14.14
6.3
9.39
2+
2+
2+
IC = inhibitory concentration
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A. A. Borghi, M. S. A. Palma
Antibiotic
Country
USA
USA
UK
UK
North Germany
UK
Austria
USA
USA
UK
UK
England
UK
North Germany
Austria
USA
UK
UK
Germany
33
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A. A. Borghi, M. S. A. Palma
TABLE V - Average concentrations of tetracycline and its byproducts detected in STPs and rivers (Jia et al., 2009)
Compound
OTC
TC
ETC
EOTC
ICTC
ATC
EACTC
*<BLD = below limit of detection
Inffluent (ng/L)
72.5
16.5
5.9
8.5
9.5
5.7
25.3
Effluent (ng/L)
3.8
1.9
< BLD*
< BLD*
6.8
<BLD*
7.6
River (ng/L)
2.2
2.1
< BLD*
< BLD*
<BLD*
<BLD*
<BLD*
35
FIGURE 4 - Products of photocatalytic degradation of tetracycline (Adapted from Mboula et al., 2012).
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A. A. Borghi, M. S. A. Palma
FIGURE 5 Degradation products of tetracycline through direct photolysis, photocatalysis with TiO2 and photocatalysis
CONCLUDING REMARKS
This paper presents multiple aspects that comprise
the study of tetracycline, ranging from production, use,
chemical reactions, treatment, environmental impact and
increasing bacterial resistance. Given the importance
of this family of antibiotics in the treatment of various
illnesses, their indiscriminate use and the general
indifference in the disposal of medicines, studies for
elimination and awareness should have greater focus by
the scientific community. Little information has been
found about the environmental impact of tetracycline;
however show alarming situations of bacterial resistance
and the presence of these drugs in drinking water.
REFERENCES
AGA, D.S. (Ed.). Fate of pharmaceuticals in the environment
and in water treatment systems. Boca Raton: CRC Press,
2008. 408 p.
A N D R E O Z Z I , R .; R A F FA E L E , M .; N I C K L A S , P.
Pharmaceuticals in STP effluents and their solar
photodegradation in aquatic environment. Chemosphere,
v.50, p.1319-1330, 2003.
37
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A. A. Borghi, M. S. A. Palma
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40
A. A. Borghi, M. S. A. Palma
ZHAO, Y.; GENG, J.; WANG, X.; GU, X.; GAO, S. Adsorption
of tetracycline onto goethite in the presence of metal cations
and humic substances. J. Colloid Interface Sci., v.361,
p.247-251, 2011a.
ZHAO, Y.; GENG, J.; WANG, X.; GU, X.; GAO, S. Tetracycline
adsorption on kaolinite: pH, metal cations and humic acid
effects. Ecotoxicology, v.20, p.1141-1147, 2011b.
Received for publication on 01st November 2012
Accepted for publication on 14th November 2013