Antimicrobial Agents
Prof. Alaa Al-Charrakh
University of Babylon
Definitions of Antibiotics
• OLD: An antibiotic is a chemical substance produced by
various species of microorganisms that is capable in
small concentrations of inhibiting the growth of other
microorganisms
• NEW: An antibiotic is a product produced by a
microorganism or a similar substance produced wholly or
partially by chemical synthesis, which in low concentrations,
inhibits the growth of other microorganisms.
Antimicrobial Agents-1
Prof. Alaa Al-Charrakh
History
Paul Ehrlich's "magic bullet": 1909, discovered "Salvarsan", chemical used to
treat syphillis. He stressed Selective toxicity as key factor in success. NOBEL:
1908
- Domagk discovered sulfa drugs like "prontosil", 1935. This drug prevented
Staph aureus infections in vivo, but not on petri plates. After Sulfa drug
success, more search for drugs. NOBEL: 1939
- Penicillin was discovered by Alexander Fleming in 1929, not commercially
developed until WWII. NOBEL:1945
- Selman Waksman: 1943, streptomycin– first aminoglycoside (Streptomyces)
against TB, coined the term “antibiotics”. NOBEL:1952
- Chloramphenicol, 1947, from Streptomyces venezuelae
- Tetracycline: 1948, from Streptomyces.
- Clinical Use - Early 1940s.
The Ideal Drug*
1. Selective toxicity: against target pathogen but not against host
–
(high) vs. and/or (low)
2. Bactericidal vs. bacteriostatic
3. Favorable pharmacokinetics: reach target site in body with effective
concentration
4. Spectrum of activity: broad vs. narrow
5. Lack of “side effects”
–
effective to toxic dose ratio
6. Little resistance development
* There is no perfect drug
Antibacterial spectrum—Range of activity
of an antimicrobial against bacteria. A
broad-spectrum antibacterial drug can
inhibit a wide variety of gram-positive and
gram-negative bacteria, whereas a
narrow-spectrum drug is active only
against a limited variety of bacteria.
Antibiotic combinations—Combinations of
antibiotics that may be used (1) to broaden
the antibacterial spectrum for empiric
therapy or the treatment of polymicrobial
infections, (2) to prevent the emergence of
resistant organisms during therapy, and (3)
to achieve a synergistic killing effect.
Bacteriostatic activity—-The level of
antimicro-bial activity that inhibits the
growth of an organism. This is determined
in vitro by testing a standardized
concentration of organisms against a
series of antimicrobial dilutions. The
lowest concentration that inhibits the
growth of the organism is referred to as
the minimum inhibitory concentration
(MIC).
Antibiotic synergism—Combinations of
two antibiotics that have enhanced
bactericidal activity when tested together
compared with the activity of each
antibiotic.
Bactericidal activity—The level of
antimicrobial activity that kills the test
organism. This is determined in vitro by
exposing a standardized concentration of
organisms to a series of antimicrobial
dilutions. The lowest concentration that
kills 99.9% of the population is referred to
as the minimum bactericidal
concentration (MBC).
Antibiotic antagonism—Combination of
antibiotics in which the activity of one
antibiotic interferes With the activity of the
other (e.g., the sum of the activity is less
than the activity of the individual drugs).
Beta-lactamase—An enzyme that
hydrolyzes the beta-lactam ring in the
beta-lactam class of antibiotics, thus
inactivating the antibiotic. The enzymes
specific for penicillins and cephalosporins
aret he penicillinases and
cephalosporinases, respectively.
Antibiotic Mechanisms of Action
Alteration of Cell
Membrane
Polymyxins
Colistin
Transcription
Translation
Translation
The main 12 classes
of Antibiotics
Mechanism of Action
1. CELL WALL SYNTHESIS INHIBITORS
Steps in synthesis:
1.
2.
3.
4.
5.
•
•
NAM-peptide made in cytoplasm
attached to bactoprenol in cell membrane
NAG is added
whole piece is added to growing cell wall
crosslinks added
the β-Lactams
the non β-Lactams
(cont’d)
Mechanism of Action
1. CELL WALL SYNTHESIS INHIBITORS
β-Lactam Antibiotics
–
–
–
–
–
Penicillins
Cephalosporins
Carbapenems
Monobactams
The clavams
(cont’d)
Mechanism of Action
CELL WALL SYNTHESIS INHIBITORS
(cont’d)
β-Lactam ring structure
Action of β-Lactam antibiotics
1. Bactericidal; growing cells only
2. Drug links covalently to regulatory enzymes called PBPs
(penicillin-binding proteins).
3. Blocks cross-linkage of peptidoglycan
Mechanism of Action
CELL WALL SYNTHESIS INHIBITORS
(cont’d)
Action of β-Lactam antibiotics
For E. coli
> MIC




wall damage
autolysins
spheroplasting
cell lysis
< MIC
 no septa
 filaments
Q: The figure below illustrating the action of penicillins on G+ ve bacterial cell wall.
Specify in each type of action, the PBPs affected.
Answer:
A-Cell lysis: All peptidoglycan hydrolases enzymes,
transglycosylases,
transpeptidases, and
carboxypeptidases.
B- Ovoid cell: Carboxypeptidases
C- Filament: Transpeptidases
Mechanism of Action
CELL WALL SYNTHESIS INHIBITORS
Resistance to β-Lactams – Gram positive
(cont’d)
Mechanism of Action
CELL WALL SYNTHESIS INHIBITORS
Resistance to β-Lactams – Gram negative
(cont’d)
Mechanism of Action
CELL WALL SYNTHESIS INHIBITORS
(cont’d)
Non - β-Lactams
 Vancomycin
active against gram positive cocci, but not gram
negative because (too large to pass through outer
membrane).
 interferes with PG elongation
 Cycloserine, ethionamide and isoniazid
inhibits enzymes that catalyze cell wall synthesis
for Mycobacterial infections
Mechanism of Action
2.
ALTERATION OF CELL MEMBRANES
1) Polymyxins and colistin (Class Polymyxins)




destroys membranes
active against gram negative bacilli
serious side effects
used mostly for skin & eye infections
2) Lipopeptides (e.g. Bacillomycin, Daptomycin, Surfactin, Echinocandins (e.g.,
caspofungin), and Iturin A)

Certain lipopeptides have strong antibacterial and antifungal activity.

Disrupt multiple cell membrane functions, leading to death.
•Q: A few drugs in class Polymyxins, Why?
•Due to structural similarity of bacterial and human cell membranes.
3- Inhibitors of protein synthesis: Sites of action
Growing polypeptide
Chloramphenicol
50S
Tetracycline
tRNA
Erythromycin
Transcription
DNA
mRNA
30S
Streptomycin
70S prokaryotic
ribosome
Direction of
ribosome travel
Inhibitors of Protein Synthesis
Selective toxicity is due to differences in ribosomes
In
human cells 80S = 60S & 40 S subunits
Bacterial
cells 70S = 50S & 30S subunits
A. Drugs that act on 30S subunit
1.Aminoglycosides – Streptomycin
Gentamicin / Amikacin
Change
shape of 30S portion & blocks initiation of translation
Are
bactericidal
Are
toxic for kidneys and ears
Poorly
absorbed from GIT – given by injections
A. Drugs that act on 30S subunit
2.Tetracyclines - Doxycycline
Minocycline
Tigecycline
Block attachment of tRNA to mRNA-ribosome
complex
•
•Are
bacteriostatic against G+ve & G-ve bacteria
mycoplasma, chlamydiae and rickettsiae
•Cause
staining of teeth in young children
B- Drugs that act on 50S subunit
1. Chloramphenicol
•Inhibit
formation of peptide bond
•Bacteriostatic
•Causes
/ Bactericidal
bone marrow suppression – aplastic anaemia
2. Macrolides
°Erythromycin,Clarythromycin,
•Prevent
movement of ribosome along mRNA
•Bacteriostatic
•One
Azithromycin.
of the least toxic drugs
4- Inhibitors of Nucleic acid synthesis
A. Inhibitors of mRNA synthesis:
Rifampicin: Inhibits mRNA synthesis by affecting DNA-dependent polymerase
of bacterial cell without affecting human cells
•
First-line anti-TB drug.
B. Inhibitors of DNA synthesis
1. Quinolones (naldixic acid)
•Inhibit
DNA gyrase which maintains the supercoiling of closed circular
DNA
•Are
broad spectrum bactericidal
2.Fluroquinolones
•Ciprofloxacin,
•Are
Ofloxacin, Sparfloxacin
broader spectrum than quinolones
•Damage
growing bones so not given to pregnant women and young children.
Mechanism of Action
INHIBITION OF DNA/RNA SYNTHESIS
(cont’d)
5. ANTI-METABOLITE ACTION
 Sulfonamides
 an analog of PABA, works by competitive
inhibition

Trimethoprim-sulfamethoxazole
 a synergistic combination; useful against UTIs
Inhibitors of DNA synthesis (anti-metabolites)
3.Sulfonamides and
trimethoprim
Para-aminobenzoic
acid (PABA)
Sulfamethxazole
Compete with PABA to
stop synthesis of folic
Dihydrofolic acid
acid which is needed for
purine synthesis. These
Trimethoprim
are used in combination
Tetrahydrofolic acid
Purines and other
precursors
DNA
6- Uncertain mechanisms of action
- Isoniazid (INH), Ethambutol, Pyrazinamide

Are first line anti-TB drugs.
- Metronidazole (Flagyl)

Probably inhibit DNA synthesis.

Bactericidal against G-ve anaerobes and Protozoa (Giardia and
Trichomonas).
Chemoprophylaxis

Is the use of antimicrobial agents to prevent infections as:
A. In normal persons exposed to pathogens

Rifampicin 600 mg twice daily during outbreaks of
meningitis.

Isoniazid (INH) to prevent TB in those recently infected.

Tetracycline to prevent plaque.
B. In persons with high susceptibility to infections
 Opportunistic infections– in immunosuppressed persons
like AIDS
 Recurrent urinary tract infections (UTI )
 Congenital and rheumatic heart diseases
C. Prior to Surgery
° Tooth extraction to prevent endocarditis
°
Colorectal surgery to prevent peritonitis and wound
infections