ANTIMICROBIAL AGENTS 5.
It should be able to remain in
ANTIBIOTICS OR
ANTIMICROBIALS
Are substances produced
from microorganisms or
synthetically that are capable of
inhibiting or destroying
microorganisms even at low
concentrations. Natural sources
include fungi & bacteria.
Ex: penicillin – derived from
the fungus Penicillium. Polymixin &
bacitracin were developed from the
bacterium bacillus sp. While
Actinomyces was the source for the
drugs tetracycline,
chloramphenicol, & streptomycin.
ANTIMICROBIAL AGENTS
~Antibiotics are mainly used in the
treatment of infectious diseases. An
ideal antimicrobial agent must
possess the following
characteristics:
1. It should be able to kill the
microbial agent or inhibit its
growth.
2. It must have a broad spectrum of
activity.
3. It should not cause any damage
or adverse effect to the patient.
4. It should remain stable when
stored in either a solid or a liquid
form.
specific body tissues long enough
for it to be effective.
6. It should be able to kill the
organism or inhibit its growth
before it has had a chance to mutate
& develop resistance.
7. It must exhibit selective toxicity.
It must be toxic to the microbial cell
but not to the host’s cells.
Classification of Antibiotics
Based on spectrum of
activity:
• Broad spectrum antibiotics –
are those with a wide coverage
of activity against a wide
spectrum of microorganisms
• Narrow spectrum antibiotics –
are those with a limited
coverage of activity, effective
only against a limited number
of microorganisms.
Based on their microbial
activity:
• Bactericidal – capable of killing
the microorganism
• Bacteriostatic – only inhibit the
growth of microorganism
Based on their
absorbability from the site
of administration:
• locally-acting antibiotic – limits
its action at the site where it is
administered.
Ex: topical agents such
ointments or eye drops
• Systemically-acting antibiotic –
affects several body systems.
Ex: antibiotics that are
 administered intramuscularly
or intravenously.
Classification of Antibiotics
According to Mechanism of
Action  membrane.
Agents that Alter the
Function or Permeability of
the Cell Membrane
 The microbial cell membrane is
essential to the survival of the
organism because not only does
it serve as a barrier by its
selective permeability but more
importantly it is the site of
bacterial ATP production.
 Agents that target the cell
membrane can be classified into
cationic, anionic, & neutral
agents.
 Cationic agents – most well-
known are polymyxin B &
colistemethate (polymyxin E).
These agents initially act by
disrupting the outer membrane
structure enabling them to enter
the cell & inhibit metabolic
processes in the bacterial cell.
 Damaging effects of polymyxin B
are:
a. Disturbance of the surface charge
& lipid composition of the cell
membrane
b. Disruption of the potassium
gradient on the cell membrane
c. Depolarization of the cell
membrane
 Antifungal drugs such as
polyenes (nystatin,
amphotericin B) alter the
permeability of the cell
 Azoles (clotrimazole,
ketoconazole, miconazole,
fluconazole), another group of
anti-fungal drugs, interfere with
the synthesis of ergosterol, a
major component of the fungal
cell membrane.
Agents that Inhibit Protein
Synthesis
 These agents bind with the
ribosomes (30S or 50S
ribosomal sub-units), results in
failure to initiate the synthesis of
proteins, interference with
protein elongation or misreading
resulting in deformed proteins.
Inhibitors of the 30S ribosomal
sub-units
 Interfere primarily with the
initiation process
 The representative drugs are the
aminoglycosides & tetracycline
 Aminoglycoside cause formation
of non-functional complexes &
misreading
 Spectinomycin is an
antimicrobial agent r/t the
aminoglycosides that bind with
30S of ribosomes different from
the target aminoglycosides.
 Tetracycline also target bacterial
30S ribosomal subunit.
 Spectinomycin & tetracycline are
only bacteriostatic but inhibit a
wide variety of bacteria
including Chlamydia & Microbial
Mycoplasma
Inhibitors of the 50S ribosomal
sub-units
 Inhibits the elongation process
of protein synthesis
 There 3 classes of drugs:
1. Chloramphenicol – acts by
binding to a peptidyl transferase
enzyme thereby inhibiting
peptide bond formation. It is a
bacteriostatic agent that is
effective against a number of
gram-positive & gram-negative
organisms.
2. Macrolides – also act on
peptidyl transferase enzyme by
interfering with its reaction or
translocation. The most popular
macrolide is erythromycin
which can effectively inhibit
certain gram-positive & gram-
negative bacteria including
Haemophilus, Mycoplasma,
Chlamydia, & Legionella. Newer
classes are: azithromycin &
clarithromycin which have
broader spectrum of activity
than erythromycin.
3. Lincinoids or lincosamines –
most important lincinoids:
clindamycin. It has a similar
target as macrolides. It is
bacteriostatic. Gentamicin &
kanamycin – binds with both
30S & 50S ribosomal subunits.
Agents that Inhibit
Metabolic
Pathways
 These agents interfere with
metabolic pathways crucial for
the survival of the
microorganism.
 Trimethoprim & sulfonamides
are antibiotics that interfere
with folic acid metabolism. They
act as competitive inhibitors of
tetrahydrofolic acid which is
important in the synthesis of
DNA, RNA, & bacterial cell wall
proteins. Bacteria cannot utilize
preformed folic acid from the
environment & thus synthesize
their own.
 Sulfonamides act specifically by
inhibiting formation of
dihydrofolic acid
 Trimethoprim inhibits formation
of tetrahydrofolic acid by
inhibiting the enzyme
dihydrofolate reductase.
Mechanisms of drug
Resistance
 An organism is said to have
developed resistance to an
antibiotic if it is not affected
anymore by that particular
antibiotic.
 Development of resistance may
either be innate (intrinsic) or
acquired
 Intrinsic resistance is a stable
genetic property that is encoded
 in the chromosome of the
organism & shared by all strains
of the species.
 Acquired resistance is
resistance arising from the
ability of an organism to resist
an antimicrobial drug to which
the species, as a whole, is
naturally susceptible. It is not
normally encoded in the
chromosome of the organism but
developed in the course of
time due to constant exposure
to the antimicrobial agent
involved. It can be due to
chromosomal mutation or the
result of genetic exchange b/w
organisms.
Several factors that
contribute to the
development of
antimicrobial resistance of
microorganisms:
• Overuse of broad-spectrum
antibiotics due to over-
prescription – most common.
• Incorrect diagnosis
• Unnecessary prescription of
antibiotics
• Indiscriminate or improper use
of antibiotics by the patient
• Use of antibiotics as additives
to livestock feeds to improve
the growth of animals
3 ways of resistance acquired
through genetic exchange
1. Transformation – is the
simplest & the earliest form of
genetic exchange. In
transformation, naked or free
microbial DNA inserts itself into the
DNA of the same species.
2. Transduction – is the transfer of
genetic material by bacteriophage.
3. Conjugation – is the transfer of
genetic material through the sex
pilus, what is transferred to another
bacterium is an extrachromosomal
DNA called plasmid. The resistance
gene is carried by the plasmid.
Mechanisms of Drug Resistance
Drug Modification or
Inactivation
Certain resistance genes may
affect the activity of an antibiotic
in two ways. A resistance gene
may code for enzymes that can
alter its chemical structure
leading to the inactivation of
the antibiotic, or the products
of the resistance genes may
cause hydrolysis of the
antibiotic thereby destroying
the antibiotic.
Example: certain bacteria
produce beta-lactamases which
can hydrolyze the beta-lactam
bonds in the chemical structure
of the antimicrobial agent – most
common mechanism in
resistance of certain
 microorganisms to penicillin &
cephalosporin
Prevention of cellular uptake
or efflux
 Gram-negative bacteria have
developed the ability to change
the lipid composition of their
outer membrane thereby
preventing the antibiotic from
reaching its cellular target. This
prevents their accumulation in
the bacterial cell.
 There are gram-negative &
gram-positive bacteria that
developed an efflux pump that
can prevent the antibiotic to
accumulate within the bacterial
cell (e.g., tetracyclines &
fluoquinolones)
 Efflux pumps are effective
against a wide range of
antimicrobials in multiple
classes.
Modification of target sites
 Antimicrobials have specific
targets in the bacterial cell.
Any change in the structure of
these target structures will
lead to the inability of the
antibiotic to exert its action
on the target bacteria.
 Example:
 the target site of penicillin on
the bacterial cell is a
structure called penicillin-
binding protein (PBP). The
organism Streptococcus
pneumonia has developed
resistance to penicillin by
causing the alteration in the
structure of its penicillin-
binding protein.
 Antimicrobial target sites that
have undergone
modifications
Target mimicry
 Is a new mechanism of
antimicrobial resistance
 It involves bacteria producing
proteins that are similar in
structure to the target sites of
the antibiotics.
 Due to similarity in structure of
the new proteins & the target
proteins, the antimicrobial binds
the new proteins & not the
target protein.
 Mycobacterium tuberculosis
produces a protein that can be
mistaken for the structure of
DNA. The protein selectively
binds fluoroquinolones
preventing its binding to the
organism’s DNA making the
organism resistant to the drug.