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Antibiotic Mechanisam of Action
Antibiotic Mechanisam of Action
3. Spectrum of Activity:
Narrow spectrum
Broad Spectrum
In these discussions, we will primarily use the functional classification, but will point out where
1. Inhibitors of Cell Wall Synthesis:
Beta-lactams:
Penicillins
Cephalosporins
Monobactams
Carbapenems
Glycopeptides
Fosfomycins
Inhibitors of Cell Wall Synthesis:
The
1928 - Penicillins
AlexanderFleming
Bread mold ( Penicillin notatum ) growing on petri dish
1939 - Florey, Chain, and Associates
Began work on isolating and synthesizing large amounts
of Penicillin.
1944 - Used in WWII to treat infections
Late 1940’s - available for general use in US
Penicillins as well as cephalosporins are called beta-lactam
antibiotics and are characterized by three fundamental
structural requirements:
the fused beta-lactam structure (shown in the blue
and red rings,
a free carboxyl acid group (shown in red bottom
right),
one or more substituted amino acid side chains
(shown in black).
The lactam structure can also be viewed as the
covalent bonding of pieces of two amino acids -
cysteine (blue) and valine (red).
The beta-lactam nucleus itself is the chief structural
requirement for biological activity;
metabolic transformation or chemical alteration of this
portion of the molecule causes loss of all significant
antibacterial activity Figure 1: beta lactam structure
Figure 2: The beta lactam ring
Mechanism of Actions of Beta
lactams
All penicillin derivatives produce their bactericidal
effects by inhibition of bacterial cell wall synthesis.
Specifically, the cross linking of peptides on the
mucosaccharide chains is prevented. If cell walls are
improperly made cell walls allow water to flow into the
cell causing it to burst.
Bacteria Cell Wall Synthesis
The cell walls of bacteria are essential for their normal
growth and development.
The peptidoglycan (which provide rigid mechanical
stability) is composed of glycan chains, which are
linear strands of two alternating amino sugars (N-
acetylglucosamine and N-acetylmuramic acid) that are
cross-linked by peptide chains. (NAG-NAM).
In gram-positive microorganisms, the cell wall is 50 to
100 molecules thick, but it is only 1 or 2 molecules
thick in gram-negative bacteria
Bacteria Cell Wall Synthesis (cont)
The biosynthesis of the peptidoglycan involves about 30 bacterial enzymes and
may be considered in three stages.
The first stage is precursor formation in the cytoplasm. The product, uridine diphosphate
(UDP)-acetylmuramyl-pentapeptide, called a " Park nucleotide “.
The last reaction in the synthesis of this compound is the addition of a dipeptide, D-
alanyl-D-alanine.
The third and final stage involves the completion of the cross-link. This is accomplished by
a transpeptidation reaction that occurs outside the cell membrane. The transpeptidase
itself is membrane bound. The terminal glycine residue of the pentaglycine bridge is
linked to the fourth residue of the pentapeptide (D-alanine), releasing the fifth residue
(also D-alanine).
Penicillin binds at the active site of the transpeptidase enzyme that cross-links the
peptidoglycan strands. It does this by mimicking the D-alanyl-D-alanine residues that
would normally bind to this site. Penicillin irreversibly inhibits the enzyme transpeptidase
by reacting with a serine residue in the transpeptidase. This reaction is irreversible and so
the growth of the bacterial cell wall is inhibited.
Bacteria Cell Wall Synthesis (cont):
The PBPs and Binding of Penicillins
Related targets of penicillins and cephalosporins collectively termed penicillin-
binding proteins (PBPs)
Glycylcyclines - Tigecycline
Ansamycins - Rifampin
(Bacteriostatic or Bactericidal depending on organism and concentration)
Inhibitors of Protein Synthesis
These classes interferes with ribosomes
Inhibit 50S ribosomal RNA near peptidyl transferase centre, thereby preventing peptide
chain elongation by blocking of polypeptide exit tunnel. As a result,m pepidyl tRNA is
dissociated from the ribosome
Active against: pneumococci, streptococci, staphylococci, H. Pyroli, Ricketssia spp,
chlamydia spp
Hemophilus influenza and Campylobacter are less susceptible
• All Bactericidal
Polymyxin Mode of Action
Target =Membrane phospholipids (lipopolysaccharides (LPS) and
lipoproteins)
1. Outer and Cytoplasmic Membrane Effect:
Polymyxins are positively charged molecules (cationic) which are attracted to the
negatively charged bacteria.
The negative charge of bacteria is due to LPS in the outer membrane and the
peptidoglycan (notably the teichoic acid).
The antibiotic binds to the cell membrane, alters its structure and makes it more
permeable. This disrupts osmotic balance causing leakage of cellular molecules,
inhibition of respiration and increased water uptake leading to cell death.
The antibiotic acts much like a cationic detergent and effects all membranes similarly.
Toxic side effects are common.
Little or no effect on Gram-positives since the cell wall is too thick to permit access to the
membrane.
Gram-positives are naturally resistant.
4. Antimetabolites
Folate Pathway Inhibitors:
Sulfonamides, Trimethoprim/Sulfamethoxazole
The drug resembles a microbial substrate and competes
with
that
substrate for the limited microbial enzyme
The drug ties up the enzyme and blocks a step in
metabolism
Synthesis of Tetrahydrofolic Acid
Humans do not
synthesize folic acid.
Good selective target
Sulfonamides
(sulfadiazine,
sulfamethoxazole,
sulfadoxine)
Bacteriostatic
Introduced in 1930’s –
first effective systemic
antimicrobial agent
Used for treatment of
acute, uncomplicated
UTI’s
Trimethoprim/Sulfamethoxaz
ole
TMP/SXT is bactericidal
Broad spectrum
Synergistic action
Anti-metabolite (conts)
The combination SXT (thrimethoprim-sulfamethoxazole)
is synergistic and the association provides a bactericidal
effect
Natural Resistance
Enterococcus – low level and poorly expressed
S. pneumoniae
Ps. aeruginosa (impermeability)
5. Inhibitors of Nucleic Acid
Synthesis (Qunolones & Furanes)
Quinolones:
Humans do synthesize DNA - shared process with
bacteria
Do tend to see some side effects with Quinolones
Some drugs withdrawn from market quickly
All are bactericidal
Quinolones
Mode of Action
Small and hydrophilic, quinolones have no problem
crossing the outer membrane.
They easily diffuse through the peptidoglycan and the
cytoplasmic membrane and rapidly reach their target.
Target = Topoisomerases (DNA-gyrase)
Rapid bactericidal activity
Quinolones inhibit DNA synthesis
Mode of Action
A typical E. coli’s chromosome is 1400 microns long (1 micron in diameter
when supercoiled), enough to fit in the E. coli’s bacterial cells which is 2-3
microns long
The bacterial chromosome consists of a single circle of DNA
DNA is double-stranded forming a left-handed double helix
All topoisomerases ( which are involved in DNA replication,
transcription and recombination) can relax DNA but only gyrase which
carry out DNA supercoiling.
The main quinolone target is the DNA gyrase which is responsible for
cutting one of the chromosomal DNA strands at the beginning of the
supercoiling process. The nick is only introduced temporarily and later
the two ends are joined back together (i.e., repaired).
• The quinolone molecule forms a stable complex with DNA gyrase
thereby inhibiting its activity and preventing the repair of DNA cuts
Resistance to Quinolones
Natural Resistance
Gram Positives – 1st generation quinolones
S.pneumoniae – decreased activity to Ofloxacin and
Ciprofloxacin
Ps. aeruginosa – decreased activity to Norfloxacin and
Ofloxacin
Furanes
Nitrofurantoin
Mode of Action:
The drug works by damaging bacterial DNA.