Antibiotic

1-Terminology
Selective Toxicity: the ability to kill or inhibit the growth of an invading microorganism
without harming the cells of the host.
Antibacterial spectrum: Range of activity of an antimicrobial against bacteria.

broad-spectrum antibacterial drug can inhibit a variety of gram-positive and

gram-negative bacteria
Narrow spectrum a drug is active against a limited variety of bacteria.

Penicillin G, for example, affects gram-positive bacteria but very

few gram-negative bacteria

A primary factor involved in antibacterial effect on gram-negative bacteria is:

The ability of drug to pass throw the lipopolysaccharide outer layer of gram-negative
bacteria and the porins that form water-filled channels across this layer
Drugs that pass through the porin channels must be: relatively small and preferably
hydrophilic.

Bacteriostatic Antibiotic that inhibits the growth of bacteria but does not
kill
Bactericidal Antibiotic that kills bacteria.

2-Major Mechanism of Action for Antibacterial Drugs

1. Inhibition of cell wall synthesis Penicillin’s,
Cephalosporins,
Vancomycin
Monobactam (Aztreonam)
bacitracin
2. Inhibition of protein synthesis: Chloramphenicol, Tetracyclines
Aminoglycoside (streptomycin)
Macrolide (erythromycin)
3. Injury to plasma membrane: polymyxin - Antifungal
4. Inhibition of nucleic acid Quinolones (ciprofloxacin -Levofloxacin)
Rifampin
replication and transcription:
5. Inhibition of essential Sulfanilamide
metabolite synthesis:
 1-Drug Inhibit Cell Wall Synthesis

1-Mechanism of Action: block the biosynthesis of peptidoglycan in bacterial cell wall by

Bind to a group of enzymes called penicillin-binding proteins (PBPs) (e.g.,
transpeptidases, transglucosylases).
Consequently, the cell wall is greatly weakened and the cell undergoes lysis by osmotic
lysis. 
2- mode of action: Bactericidal but only actively growing cells are affected by these
antibiotics.
3- Selective Toxicity: Because human cells (Eukaryote) do not have a peptidoglycan cell
wall.
4- Mechanism of resistance: bacteria can resist the action of this group by:
(1) an overproduction of PBP enzymes
(2) acquisition of a new PBP enzyme
(3) bacteria can produce β-lactamases that inactivate the β-lactam antibiotics

5- Examples:
β-Lactam antibiotics Ohers
Penicillin’s Glycopeptides (Vancomycin)

Cephalosporin  Bacitracin

Monobactams (Aztreonam)

Carbapenems (Imipenem, meropenem)

 Penicillin’s
Chemical Structure β-Lactam antibiotic - characterized by the presence of a β-
lactam ring found within the central structure of the drug
molecule and 1 R side chain.
Mechanism of Action Cell wall synthesis inhibition (prevent the cross-linking of
the peptidoglycans)

Inactive against organisms devoid of a peptidoglycan cell

wall, such as mycoplasma, protozoa, fungi, and viruses.

Mode of action: Bactericidal

There are 2 Major types of Penicillin’s

(a)Natural Penicillin’s
Source Extracted from Cultures of The Mold Penicillium
Examples Penicillin G (requires injection) the prototype compound of
all the penicillin’s

Penicillin V (can be taken orally)

Spectrum of Activity narrow spectrum
the drug of choice against:
Streptococci
Staphylococci (none penicillinase producing staph.),
Several spirochetes (T.Pallidum)
Very few gram-negative bacteria
disadvantages 1- narrow spectrum
2- Hypersensitivity
3- Susceptibility to penicillinases.

Penicillinases are one of (β-lactamases enzymes) produced by many bacteria, most

notably Staphylococcus species, that cleave the β-lactam ring of the penicillin molecule.

A large number of modifications in natural penicillin’s have been developed in attempts

to overcome the disadvantages of natural penicillin’s and this attempt’s come out with a
large number of semisynthetic penicillins.
(b)Semisynthetic penicillins.
1- Penicillinase-Resistant Penicillin’s  Similar to the natural penicillin’s, except that
were relatively resistant to Penicillinase enzyme

Methicillin,
Nafcillin It can be used for of staphylococcal
Oxacillin Infections.
Cloxacillin
but resistance to them also soon appeared;
thus, the organisms were termed methicillin-
resistant Staphylococcus aureus (MRSA)

2-Extended-Spectrum Penicillins Adding amino group (NH2) to natural penicillin’s

Overcome the problem of the narrow spectrum
(Amino Penicillins) of activity.
Ampicillin Effective against many gram-negative bacteria
Amoxicillin as well as gram-positive ones, although they
are not resistant to penicillinases.

3- Penicillins Plus β-Lactamase combine penicillins with one of β-Lactamase

Inhibitors  Inhibitors (potassium clavulanate (clavulanic
acid)- sulbactam – tazobactam)
Unasyn =
(ampicillin + sulbactam) It has been combined the Extended -spectrum
of amino-penicillins, and the resistant to
Augmentin = penicillinases
(amoxicillin+ clavulanate)
improved activity against β-lactamase–
producing staphylococci and selected gram-
Tazocin = negative rods
(piperacillin-tazobactam)

β-Lactamase Inhibitors (potassium clavulanate (clavulanic acid)) – sulbactam –

tazobactam are a noncompetitive inhibitor of penicillinase with essentially no
antimicrobial activity of its own.
 Cephalosporins
Chemical Structure β-Lactam antibiotic - However, the β-lactam ring of cephalosporins is
fused to a six-member ring, rather than the five-member ring found in
penicillins. This chemical difference provides cephalosporins with an
increased resistance to enzymatic inactivation by β-lactamases.
cephalosporin C possesses two R groups, compared with just one R
group for penicillin, and this provides for greater diversity in chemical
alterations and development of semisynthetic cephalosporins.  
Mechanism of Action Cell wall synthesis inhibition (prevent the cross-linking of the
peptidoglycans)

they have a wider antibacterial spectrum, more resistant to many β-

lactamases, and have improved pharmacokinetic properties when
compared with penicillin’s

Mode of action: Bactericidal

There are five generations of cephalosporins.

First-generation (cephalexin, cephalothin, cefazolin, cefadroxil, cephradine)

Narrow spectrum - Activity against gram-positive bacteria (equivalent to

oxacillin and Methicillin); limited activity to gram-negative.
do not cross the blood-brain barrier (BBB)

Second-generation (Cefaclor, Cefuroxime- Cefoxitin- Cefotetan)

Expanded-spectrum - Activity against gram-positive bacteria (equivalent
to oxacillin and Methicillin) More extended gram-negative spectrum and
anaerobic bacteria (cefoxitin - Cefotetan)

do not cross the blood-brain barrier except Cefuroxime

Third-generation Cefdinir, Cefixime, Cefotaxime, Ceftazidime, Ceftibuten,
Ceftriaxone
Broad spectrum - Have significantly increased activity against gram-
negative bacilli, with some of these agents active against Pseudomonas
aeruginosa.

Can cross the blood-brain barrier can be used to treat meningitis.

*Anti-Anaerobic Antimicrobial Agents: is second generation (Cefoxitin, Cefotetan)

Fourth-generation (Cefepime,)

extended spectrum - Have extended activity against both gram-positive

and gram- negative organisms include P. aeruginosa.
cross the blood-brain barrier (BBB)

Fifth-generation (Ceftaroline(
used to treat bacteria, including resistant Staphylococcus aureus
(MRSA) and Streptococcus species, that are resistant to penicillin
antibiotics.

cross the blood-brain barrier 

Glycopeptides (Vancomycin)
Chemical Structure complex glycopeptide
Mechanism of Action inhibits synthesis of bacterial cell wall phospholipids as well
peptidoglycan polymerization at an earlier step than that inhibited by B-
se lactam antibiotics.

prevents cell wall synthesis of the long polymers of  (NAM) and (NAG) that form
the backbone strands of the bacterial cell wall
Mode of action: Bactericidal

Spectrum Narrow spectrum

Vancomycin is useful in patients with serious allergic reactions to B-
lactam antibiotics.

Effective against multidrug-resistant organisms such as methicillin.

resistant staphylococci aurues (MRSA).

Vancomycin is ineffective against gram-negative bacteria.

 Bacitracin
Chemical Structure Polypeptide
Mechanism of Action inhibits the synthesis of cell walls at an earlier stage than penicillins and
cephalosporins.

Bacitracin interferes with the dephosphorylation of a lipid molecules which function

as membrane carrier molecules that transport the building-blocks of
the peptidoglycan bacterial cell wall outside of the inner membrane

Mode of action: Bactericidal

Spectrum  Narrow spectrum- It targets Gram-positive organisms, especially

those that cause skin infections.( Staphylococcus aureus -
Staphylococcus epidermidis – Streptococcus pyogenes ) 

bacitracin is used to distinguish S. pyogenes from other β-hemolytic

streptococci.(  S. pyogenes being sensitive to bacitracin and others resistant.) 

Limitation Its use is restricted to topical application for superficial infections.

since bacitracin is nephrotoxic and its concentration in the blood must
be followed closely.

2. Drug Inhibiting Protein Synthesis

1-Mechanism of Action: (Inhibiting Protein Synthesis). It work at different stages of 

proteins translation process , like initiation, elongation and termination .

2- Selective Toxicity: The cytoplasmic ribosomes found in animal cells (Eukaryote) (80S)

(60s subunit + 40s subunit) are structurally distinct from those found in bacterial cells
(70S) (50s subunit +30s subunit), making protein biosynthesis a good selective target
for antibacterial drugs.

Most of this drug can be grouped into 2 main categories:

Antibiotics bind to the 30S subunit of the ribosome Aminoglycosides - Tetracyclines

Antibiotics bind to the 50S ribosomal subunit Macrolides - Chloramphenicol

 Aminoglycosides
Chemical Structure consist of amino sugars linked through glycosidic bonds to an
aminocyclitol ring.
Mechanism of Action inhibit bacterial protein synthesis by irreversibly binding to the 30S
ribosomal subunit. (change shape of 30s – incorrect reading mRNA)

Mode of action: Bactericidal (concentration-dependent)

Spectrum  Narrow spectrum- activity against Gram-negative aerobes and

facultative anaerobic bacilli" 

 not active against gram-negative anaerobes and most gram-
positive bacteria
Example Streptomycin, Neomycin, Kanamycin, Tobramycin, Gentamicin,
Amikacin

Note: These antibiotics exert their effort by passing through the bacterial outer membrane (in gram-
negative bacteria), cell wall, and cytoplasmic membrane, Penetration through the cytoplasmic
membrane is an aerobic, energy-dependent process, so anaerobes are resistant to aminoglycosides

Macrolides
Chemical Structure macrocyclic lactone ring bound to two sugars,
Mechanism of Action inhibit bacterial protein synthesis by their reversible binding to the 50S
ribosomal subunit, which blocks polypeptide elongation.

Mode of action: Bacteriostatic (concentration-dependent)

Classes & Spectrum Erythromycin, spectrum of activity is similar to that of penicillin G, and it is a
frequent alternative drug to penicillin, it used to treat infections caused gram-
positive bacteria in patients allergic to penicillin.

Most gram-negative bacteria are resistant to the Erythromycin.

Other macrolides now available include azithromycin and clarithromycin.

have a broader antimicrobial spectrum, compared to erythromycin.

Example Erythromycin, Azithromycin, Clarithromycin.

Chloramphenicol – binds to 50s protein and inhibit formation of Peptide bond.

Tetracycline – interfere with attachment of tRNA to mRNA – ribosome complex

 3. Drugs cause Injury to plasma membrane

1-Mechanism of Action: this drugs target plasma membrane to disrupt the membrane.
producing increased cell permeability and eventual cell death.
This mode of action can be seen in:

Small Group of polymyxin B and polymyxin E (colistin)

Antibacterial 
 They have detergent-like properties that interact with the
lipopolysaccharide component of the outer membrane of gram-negative
bacteria, ultimately disrupting both their outer and inner membranes
and killing the bacterial cells.

the membrane-targeting mechanism is not a selective toxicity, it

causing serious nephrotoxicity.

Thus, their use has been limited to Topical external treatment of

localized infections such as external otitis, eye infections, and skin
infections.

These antibiotics are most active against gram-negative rods, because

gram-positive bacteria do not have an outer membrane.

Some Antifungal amphotericin B, miconazole, and ketoconazole

Drugs Such drugs combine with sterols in the fungal plasma membrane to
disrupt the membrane.

Selective Toxicity - it targets a specific type of sterols called

(ergosterol). I
in fungal membranes the principal sterol is ergosterol; but in animal
membranes, cholesterol.

Bacteria are resistant to Antifungal, because bacterial plasma

membranes generally lack sterols.
 4. Drugs cause Inhibition of nucleic acid replication and transcription.
1-Mechanism of Action: inhibiting nucleic acid synthesis, replication, transcription,
recombination, and repair by blocking certain Enzymes needed for these processes.
2- mode of action: All quinolones are bactericidal against the majority of gram-negative
bacteria.
3- Selective Toxicity: The nucleic acid replication and transcription enzymes in bacteria
are structurally different from those in eukaryotes.
4- Examples
Quinolones
Rifampin

Quinolones
Chemical Structure
Mechanism of Action inhibiting the replication of bacterial DNA by interfering with the action of
DNA gyrase (topoisomerase II) during bacterial growth.

Mode of action: Bactericidal

Classes & Spectrum first quinolone - nalidixic acid. This drug was used to treat urinary tract
infections caused by a variety of gram-negative bacteria, not active
against gram positive.

Chemical modifications to the original quinolone backbone have resulted in the

production of:

Fluoroquinolones - such as ofloxacin, norfloxacin, ciprofloxacin, and

moxifloxacin are broad-spectrum antibiotics that have excellent activity
against gram-positive and gram-negative

It used in a broad range of bacterial infections-such as pneumonia and

tuberculosis (TB).

Example nalidixic acid, ofloxacin, norfloxacin, ciprofloxacin, moxifloxacin

Which of the following terms refers to the ability of an antimicrobial drug to harm the
target microbe without harming the host?
 a. mode of action
b. therapeutic level
c. spectrum of activity
d. selective toxicity
Show Answer
Which of the following is not a type of β-lactam antimicrobial?
a. penicillins
b. glycopeptides
c. cephalosporins
d. monobactams
Show Answer
Which of the following does not bind to the 50S ribosomal subunit?
a. tetracyclines
b. lincosamides
c. macrolides
d. chloramphenicol
Show Answer
Which of the following antimicrobials inhibits the activity of DNA gyrase?
a. polymyxin B
b. clindamycin
c. nalidixic acid
d. rifampin
Show Answer