Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5704_Библиотеки_им_академика_М_И_Перельмана
.pdf
Targeted Viral and Microbial Enzymes 39
Dibekacin (sulfate)
Its structure corresponds to 3’,4’-dideoxykanamycin B. It is active against
enterobacteria, Pseudomonas and certain strains of staphylococci. This product is
used to treat severe urinary tract infections.
Tobramycin (sulfate)
Its structure corresponds to 2’-amino 2’,3’-dideoxykanamycin B. Its activity is
similar to that of Gentamycin, but better on Pseudomonas aeruginosa.
https://t.me/med1917
40 Enzymes and Drugs
Gentamycin (sulfate)
It is a mixture of three compounds with ose-genin-ose bonds, with gentosamine
(4-methyl-3-methylaminodeoxypentose) and osamine (2,6-diamino-2,3,4,6-
deoxyglucose) as oses.
The antibacterial spectrum is superior to that of other products in this group. This
product is effective against GRAM – bacteria: E. coli, Enterobacter, Klebsiella,
Serratia, Salmonella, Shigella and Pseudomonas aeruginosa, as well as GRAM +
cocci: Streptococcus and Staphylococcus meti-S. This compound is used
intramuscularly in urinary tract infections, pulmonary infections, severe meningitis
and life-threatening septicemia.
Sisomicin (sulfate) and Netilmicin (sulfate)
Sisomicin (R = H) has a spectrum corresponding to that of Gentamycin, with
superior activity in enterococcal infections. Netilmicin (R = C
2
H
5
) is the
hemisynthetic derivative prepared by alkylation of the amine function of Sisomicin.
Their antibacterial spectrum is close to that of Gentamycin.
https://t.me/med1917
Targeted Viral and Microbial Enzymes 41
NOTE.– The use of aminoglycosides is reserved for serious, life-threatening
infections where other antibiotics cannot be used, and after careful assessment of the
benefits against the risks of auditory and renal toxicity. They are used parenterally,
as they are inactive orally due to their degradation. As they are water-soluble, they
do not cross the blood–brain barrier and are inactive in the treatment of central
nervous system infections.
Synergistic combinations of aminoglycosides with beta-lactams, whose effect on
the wall favors the action of aminoglycosides, should be noted (in the case of
streptococcal and staphylococcal endocarditis and GRAM – infections), as well as in
immunocompromised patients with agranulocytosis.
Four and five diosides: neomycins, paromomycin (derivatives of
ribostamycin, the latter not being used therapeutically)
These compounds are used in digestive disorders, infectious and parasitic
diarrhea, as well as ear and eye infections.
2.2.2.3.2. Antibiotics acting on the 50S ribosomal sub-unit
Chloramphenicol, Thiamphenicol and Florfenicol, known as phenicols, are also
inhibitors of protein synthesis.
By binding irreversibly to the 50S sub-unit, they prevent protein synthesis.
Thiamphenicol is used in human medicine for salmonellosis, biliary infections,
respiratory infections and Haemophilus influenzae. Enterococci, staphylococci,
streptococci, Salmonella, Shigella, Aeromonas, Klebsiella, Enterobacter and
Escherichia coli are sensitive to this bacteriostatic agent. Acinetobacter,
Pseudomonas, Providencia, Serratia and mycobacteria are resistant to it.
Chloramphenicol is used against the same pathogens, but its indications are limited
https://t.me/med1917
42 Enzymes and Drugs
to a small number of countries, due to hematological side effects. Florfenicol is a
very broad-spectrum bacteriostatic used in veterinary medicine, especially in cattle
and pigs.
Macrolides and lincosamides are structurally distinct molecules, whose modes of
action lead them to be grouped together. They act as bacteriostatic agents, disrupting
the function of the 50S sub-unit of bacterial ribosomes. These molecules are highly
lipid-soluble and have very good tissue distribution.
Macrolides are macrocyclic derivatives with a lactone or olid residue.
Macrolides, such as Erythromycin, Azithromycin, Telithromycin, Spiramycin,
Midecamycin, Josamycin or Tilmicosin (the latter only used in veterinary medicine)
are active against GRAM + bacteria (Corynebacterium, Listeria, Staphylococcus,
Streptococcus, etc.) and GRAM – bacteria (Campylobacter, Actinobacillus, etc.).
Anaerobic germs (Actinomyces, Clostridium, Bacteroides, etc.), germs with
obligatory intracellular development, such as chlamydia, and certain mycoplasmas
are also sensitive. Enterobacteriaceae and Pseudomonas are resistant.
Erythromycin was the first derivative of this family of antibiotics. Other
compounds were subsequently introduced, including Azithromycin. Clarithromycin,
Dirithromycin and Cetromycin, whose structures are not reported, are macrolides
with the same mode of action as Erythromycin.
The antibacterial spectrum targets GRAM + cocci and, in particular,
streptococci. Clostridia, Listeria, Chlamydia trachomatis, Legionella and
https://t.me/med1917
Targeted Viral and Microbial Enzymes 43
Mycoplasma pneumoniae are also sensitive to this compound. Its indications are
similar to penicillin.
Azithromycin no longer has the ketone function of Erythromycin and has an
N-methyl residue.
This macrolide’s spectrum extends to GRAM-negative bacteria: Haemophilus
influenzae, Branhamella catarrhalis and intracellular germs: Chlamydia
pneumoniae, Mycoplasma pneumoniae. Its main indications are sore throats,
bronchitis and urethritis.
Telithromycin is a hemisynthetic derivative of erythromycin, belonging to a new
group of compounds known as Ketolides.
It has antibacterial activity against GRAM-positive cocci (Streptococcus
pneumoniae) and GRAM-negative bacteria (Haemophilus influenzae, Moraxella
catarrhalis), as well as certain sensitive atypical germs. It is used to treat severe
pneumonia or bronchitis, sinusitis and tonsillitis caused by sensitive germs resistant
to penicillin or erythromycin.
https://t.me/med1917
44 Enzymes and Drugs
Spiramycin is a mixture of three derivatives (macrolides), isolated from
Streptomyces ambofaciens. Its mode of action is the inhibition of protein synthesis
through its action on the 50S ribosome. It acts on GRAM-positive aerobic germs
(indications for macrolides) and is used in the prophylaxis of meningococcal
meningitis.
Midecamycin, which is similar to the previous antibiotic, has the general
indications of macrolides for sensitive germs.
Josamycin is also a macrolide. The compound is extracted from Streptomyces
narbonensis var. josamyceticus. Its spectrum of activity and therapeutic indications
are similar to those of Erythromycin.
Lincosamides (Figure 2.16), including Lincomycin and Clindamycin, are active
against GRAM + bacteria, anaerobes and mycoplasmas. Many GRAM – bacteria
are resistant. Lincosamides can antagonize the action of Chloramphenicol,
Erythromycin and Tilmicosin.
https://t.me/med1917
Targeted Viral and Microbial Enzymes 45
The lincosamides are related to the macrolides and have two representatives.
Their structure is derived from N-methytlproline and galactopyranose thiomethyl
ether.
Lincomycin is an antibiotic isolated from Streptomyces lincolnensis. Its spectrum
includes GRAM + cocci, GRAM + bacilli and, in particular, staphylococci. Its
mechanism of action is bactericidal, acting like Erythromycin on protein synthesis at
the 50S sub-unit of the ribosome. Its indications are GRAM + cocci infections
(streptococci and staphylococci) and the treatment of osteomyelitis (due to very
good bone diffusion).
Clindamycin is a hemisynthetic derivative. It has a broader spectrum,
encompassing Cocci GRAM – (gonococcus) and bacteroids. Its indications are
similar to those of Lincomycin.
Figure 2.16. Structure of lincosamides
2.2.2.4. Carboxypeptidases (EC 3), transpeptidases (EC 2),
transglycosylases (EC 2), endopeptidases (EC 3) (Penicilline Binding
Proteins – PBPs) and beta-lactamases (EC 3)
2.2.2.4.1. PBPs
The latter are involved in peptidoglycan synthesis. They belong to the
Penicillin-Binding Proteins (PBP) family. They catalyze transglycosylation,
transpeptidation, carboxypeptidation and endopeptidation reactions (Sauvage et al.
2008). Certain molecules from the penicillin family are able to bind to these
enzymes once they have crossed the bacterial wall.
Molecules with a β-lactam ring have a structural analogy with the D-Ala-D-Ala
unit of peptidoglycan. They are able to bind to the enzymatic domains recognizing
this dipeptide part.
The enzyme opens the beta-lactam ring, but is unable to complete the reaction. A
stable acyl-enzyme complex is formed. This is why β-lactams are considered to be
https://t.me/med1917
46 Enzymes and Drugs
suicidal substrates for these enzymes. Antimicrobial activity results from a covalent
bond between the antibiotic and the active sites of one or more groups of enzymes
corresponding to PBPs (Duguide 1946; Park and Strominger 1957; Spratt 1983;
Tipper 1985).
Antibiotics containing the β-lactam group (penicillins, cephalosporins and
monobactams) are PBP inhibitors. They exert their antibacterial activity by
inhibiting the peptidoglycan assembly stages of their walls (cross-linked polymers).
When they are well structured, these polymers impart bacteria rigidity and resistance
(Barreteau et al. 2008; Drawz and Bonomo 2010).
Penicillins, such as Benzylpenicillin and its derivatives, are sensitive to
beta-lactamases which, when present, inactivate these antibiotics. Aminopenicillins
(such as Ampicillin and Amoxicillin) and cephalosporins (such as Cefalexin, Ceftiofur,
Cefotaxime) are generally more resistant to bacterial beta-lactamases. It should be noted
that resistance to penicillins exists in certain GRAM + bacteria, in particular certain
strains of Staphylococcus aureus. These bacteria produce extracellular beta-lactamases.
Many GRAM – germs are also resistant. Benzylpenicillin derivatives are a priori active
against a number of GRAM + bacteria (including beta-hemolytic streptococci), certain
GRAM + and GRAM – anaerobic bacteria (Clostridium, Fusobacterium or
Bacteroides) and, finally, GRAM – germs (Haemophilus, Pasteurella, Actinobacillus).
Vancomycin is an amphoteric glycopeptide. This antibiotic is extracted from
Streptomyces orientalis cultures. Its structure comprises a heptapeptide, amino acid
residues, aromatic rings and a disaccharide consisting of glucose and vancosamine.
Its antibiotic activity is exerted through inhibition of bacterial wall biosynthesis, by
https://t.me/med1917
Targeted Viral and Microbial Enzymes 47
binding to the terminal D-Ala-D-Ala group, with inhibition of transglycosylases and
transpeptidases.
2.2.2.4.2. Beta-lactamases
These are peptidases that split the lactam bond, transforming penicillins and
cephalosporins into derivatives with no antibacterial effect.
Bacterial resistance to treatment of infections with penicillins and cephalosporins
is linked to the secretion of beta-lactamases and cephalosporinases by bacteria.
These serine enzymes act on the beta-lactam ring of these antibiotics and lead to
their opening, forming derivatives with no antibacterial activity (Tipper 1985;
Sauvage et al. 2008; Drawz 2010) (Figure 2.17).
Figure 2.17. Action of a beta-lactamase inhibitor
The combination of beta-lactamase inhibitors with penicillins and cephalosporins
prevents the degradation of the beta-lactam ring of these antibiotics and enables
antibacterial activity to be maintained.
Solutions to the problem of bacterial resistance through the secretion of
beta-lactamases have been approached in two ways, as shown in Figure 2.18:
– preparation of a large number of new beta-lactam penicillins and
cephalosporins, represented in a condensed form by their typical general structure in
Figure 2.18;
– synthesis of beta-lactamase inhibitors that prevent the opening of the β-lactam
ring and consequently the loss of activity.
Beta-lactam antibiotics
Antibiotics containing a beta-lactam group are derivatives of the four-membered
nitrogen heterocycle or azetidine, forming azetidine-2-one, which leads to most
penicillins, cephalosporins and beta-lactamase inhibitors (Figure 2.18).
https://t.me/med1917
48 Enzymes and Drugs
Structural considerations
Figure 2.18. General structure of penicillins,
cephalosporins and beta-lactamase inhibitors
Penicillins
The structure of penicillins comprises an azetidine-2-one ring (beta-lactam
group) and a thiazolidine ring with a common side. They are amides of
6-aminopenicillanic acid with three chiral centers. Two natural derivatives,
Benzylpenicillin and Phenoxymethylpenicillin (penicillin V), are obtained by
extraction from the culture media of various penicilliums. The same applies to
6-amino-penicillanic acid. The latter is also prepared by hydrolysis of the amide
bonds of various natural penicillins and by total synthesis. It is used as a raw
material in the preparation of various synthetic penicillins by amidification of the
6-amine group.
https://t.me/med1917
Соседние файлы в папке Библиотека им академика М.И. Перельмана