Antibiotics
STRUCTURE, SYNTHESIS AND BIOLOGICAL EFFECTS
Definition and classification
An antibiotics are the agent that either kills or inhibits the growth of a microorganism by
biochemical process. The term antibiotic was first used in 1942 by Selman Waksman and his
collaborators in journal articles to describe any substance produced by a microorganism that
is antagonistic to the growth of other microorganisms in high dilution.
Antibiotics that kill bacteria are called "bactericidal"
Antibiotics that stop the growth of bacteria are
called "bacteriostatic"
Selman Abraham Waksman
1888 - 1973
Antibiotics are commonly classified based on their
• mechanism of action,
• chemical structure,
• spectrum of activity.
Most antibiotics target bacterial functions or growth processes. Antibiotics that target the bacterial cell wall (penicillins,
cephalosporins), or cell membrane (polymixins), or interfere with essential bacterial enzymes (quinolones, sulfonamides) are
usually bactericidal in nature.
Those that target protein synthesis, such as the aminoglycosides, macrolides, and tetracyclines, are usually bacteriostatic.
Further categorization is based on their target specificity: narrow-spectrum antibiotics target particular types of bacteria, such
as Gram-negative or Gram-positive bacteria, while broad-spectrum antibiotics affect a wide range of bacteria.
Gram-staining: A test, resulting in the classification of bacteria, developed in the last century by Hans Christian Gram, a Danish
microbiologist:
- Gram positive bacteria will retain the original blue stain
- Gram negative bacteria will lose the blue stain upon intermediate acetone treatment and will stain red
Gram staining differentiates bacteria by the chemical and physical properties of their cell walls by detecting peptidoglycan,
which is present in a thick layer in gram-positive bacteria. In a Gram stain test, gram-positive bacteria retain the crystal violet
dye, while a counterstain (commonly safranin or fuchsin) added after the crystal violet gives all gram-negative bacteria a red or
pink coloring.
The Gram staining is a valuable diagnostic tool in both clinical and research settings, not all bacteria can be definitively
classified by this technique.
Classes of antibiotics
β-Lactam antibiotics
Alexander Fleming
1881 - 1955
Penicillium notatum
1928: A. Fleming discovered that his cultures of staphylococci was contaminated with a fungus, and that
the colonies of staphylococci immediately surrounding the fungus had been destroyed, whereas other
staphylococci colonies farther away were normal. This fungi was the Penicillium notatum which
produced a bactericidal agent.
The penicillins are the oldest of the clinical antibiotics, but are still the most widely used. The first of the
many penicillins to be employed on a significant scale was penicillin G (benzylpenicillin), obtained from
the fungus Penicillium chrysogenum by fermentation in a medium containing corn-steep liquor. The αaminoadipyl side-chain of isopenicillin N is removed and replaced by another acid according to its
availability from the fermentation medium. Several other penicillins are accessible by supplying different
acids.
Synthesis of penicillins by fermentation
Penicillin is a secondary metabolite of certain species of Penicillium and is produced when growth of the fungus is inhibited
by stress. It is not produced during active growth. Penicillin is produced by the fungus Penicillium
chrysogenum which requires lactose, other sugars, and a source of nitrogen (in this case a yeast
extract) in the medium to grow well.
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Semisynthesis" or partial chemical synthesis: compounds isolated from natural sources (e.g. plant material or bacterial or cell
cultures) are used as starting materials. Semisynthesis is usually used when the precursor molecule is too structurally complex,
too costly or too inefficient to be produced by total synthesis. It is also possible that the semisynthetic derivative outperforms
the original biomolecule itself with respect to potency, stability or safety.
Cloxacillin and temicillin are antibiotic useful for the treatment of a number of bacterial infections. These are semisynthetic
and in the same class as penicillin. Both compounds have large R chain, which does not allow the beta-lactamases to bind.
This drug has a weaker antibacterial activity than benzylpenicillin, and is devoid of serious toxicity except for allergic
reactions.
Penicillins and other β-lactam drugs exert their antibacterial
effects by binding to proteins (penicillin-binding proteins),
peptidase enzymes that are involved in the late stages of the
biosynthesis of the bacterial cell wall. Cross-linking of the
peptidoglycan chains which constitute the bacterial cell wall
involves a terminal D-Ala–D-Ala intermediate which, in its
transition state conformation, closely resembles the
penicillin molecule. As a result, the penicillin occupies the
active site of the enzyme and becomes bound via an activesite serine residue, this binding causing irreversible enzyme
inhibition and cessation of cell wall biosynthesis. Growing
cells are then killed due to rupture of the cell membrane and
loss of cellular contents. The bacterial cell wall has no
counterpart in mammalian cells, and the action is thus very
specific.
Antibiotic resistence
Antibiotic resistance is a form of drug resistance whereby some (or, less commonly, all) sub-populations of a microorganism,
usually a bacterial species, are able to survive after exposure to one or more antibiotics; pathogens resistant to multiple
antibiotics are considered multidrug resistant (MDR) or, more colloquially, superbugs.
Antibiotic resistance is a serious and growing phenomenon in contemporary medicine and has emerged as one of the preeminent public health concerns of the 21st century, in particular as it pertains to pathogenic organisms (the term is especially
relevant to organisms that cause disease in humans).
b-laktamase inhibitors
Amoxacillin + clavulanic acid
A β-lactamase inhibitor (or beta-lactamase inhibitor) is a molecule used in conjunction with a β-Lactam antibiotic to extend its
spectrum of activity. Although β-lactamase inhibitors have little antibiotic activity of their own, they instead inhibit the activity
of β-lactamases, a family of enzymes that break the beta-lactam ring that allows penicillin-like antibiotics to work, thereby
conferring bacterial resistance.
Aminoglycosides
The aminoglycosides form an important group of antibiotic agents and are immediately recognizable as modified carbohydrate
molecules. Typically, they have two or three uncommon sugars, mainly aminosugars, attached through glycoside linkages to an
aminocyclitol, i.e. an amino-substituted cyclohexane system, which also has carbohydrate origins.
The aminoglycoside antibiotics have a wide spectrum of activity, includingactivity against some Gram-positive and many Gramnegative bacteria. They must be administered by injection. The widespread use of aminoglycoside antibiotics is limited by their
nephrotoxicity, which results in impaired kidney function, and by their ototoxicity, which is a serious side-effect and can lead to
irreversible loss of hearing. The aminoglycoside antibiotics interfere with protein biosynthesis.
Cyclic peptide antibiotics
The cyclosporins are a group of cyclic peptides produced by
fungi such as Cylindrocarpon lucidum and Tolypocladium
inflatum. These agents show a narrow range of antifungal
activity , but high levels of immunosuppressive and antiinflammatory activities. It is now widely exploited in organ
and tissue transplant surgery to prevent rejection following
bone-marrow, kidney, liver, pancreas, lung, and heart
transplants. It has revolutionized organ transplant surgery,
substantially increasing survival rates in transplant patients.
Cyclosporin A
Glycopeptide antibiotics
Bleomycin is a mixture of glycopeptide antibiotics isolated
from cultures of Streptomyces verticillus, and used for its
anticancer activity . Bleomycin is a DNA-cleaving drug,
causing single and double strand breaks in DNA.
Vancomycin is frequently the last-resort agent in the control
of methicillinresistant Staphylococcus aureus (MRSA), since
many strains have become resistant to all other antibiotics. It
has activity against Gram-positive bacteria, especially
resistant strains of staphylococci, streptococci, and
enterococci.
Bleomycin
Vancomycin
Macrocyclic lactone antibiotics
The macrolide antibiotics are macrocyclic lactones with a ring
size typically 12–16 atoms, and with extensive branching
through methyl substituents. Polyene macrolides are larger in
the range 26–38 atoms. The largest natural macrolide
structure discovered has a 66-membered ring. Two or more
sugar units are attached through glycoside linkages; these
sugars tend to be unusual 6-deoxy structures often restricted
to this class of compounds. Macrolides are protein synthesis
inhibitors.
eritromicin
Erythromycin activity is predominantly against Grampositive bacteria, and the antibiotic is prescribed for
penicillinallergic patients
Polyene macrolides
Most polyene macrolides have antifungal properties, but
not antibacterial activity. The macrolide ring size ranges
from 26 to 38 atoms, and this also accommodates a
conjugated polyene of up to seven E double bonds.
Amphotericin is active against most fungi and yeasts, but it
is not absorbed from the gut, so oral administration is
restricted to the treatment of intestinal candidiasis.
It is administered intravenously for treating potentially lifethreatening systemic fungal infections.
Tetracycline antibiotics
Antracycline antibiotics
The tetracyclines are a group of broad-spectrum, orally active
antibiotics produced by species of Streptomyces, and several
natural and semisynthetic members are used clinically.
Their antimicrobial activity arises by inhibition of protein
synthesis. Although the tetracycline antibiotics have a broad
spectrum of activity spanning Gram-negative and Grampositive bacteria, their value has decreased as bacterial
resistance has developed in pathogens such as Pneumococcus,
Staphylococcus, Streptococcus, and E. coli.
A number of anthracycline antibiotics, e.g. doxorubicin (one
of the most successful and widely used antitumour drugs)
from Streptomyces peuceticus and daunorubicin from
Streptomyces coeruleorubicus, have structurally similar
tetracyclic skeletons and would appear to be related to the
tetracyclines. However,
anthraquinone derivatives are
intermediates in anthracycline biosynthesis, and the fourth
ring is constructed later.
chlortetracycline
doxorubicin