ANTIBACTERIALS

CHEMOTHERAPY :

•Chemotherapy can be defined as the use

of chemical compounds in the treatment
of infectious disease so as to destroy the
offending organisms or parasites without
damaging the host cells.

•Antibacterials can be antibiotics but all

antibiotics can not be antibacterials.
ANTIBIOTICS :

Antibiotics are substances produced

by various species of
microorganisms (bacteria, fungi,
actinomycetes) that suppress the
growth of other microorganisms and
eventually may destroy them.
However, the term commonly
extends to include the synthetically
prepared agents like quinolones also.
DISINFECTANTS :
 

Agents used on inanimate objects

- Sterilization of surgical instruments
e.g. Carbolic acid
 
ANTISEPTICS:
 

Agents used on living surface

- Kill or arrest the bacterial growth on
skin wounds e.g. Savlon, Dettol
 Terminology
Bacteriostatic: Bacteriostatic drug is the one which
inhibits growth of the bacteria but does not kill it e.g.
tetracycline

Bactericidal: Bactericidal drug is the one which kills

the bacteria particularly in multiplication phase e.g.
penicillins, quinolones

MIC : Minimum Inhibitory Concentration (MIC) is

the minimum concentration of a drug required to
inhibit the bacteria (mcg/ml)

MIC90 : It is the minimum inhibitory concentration

required to inhibit the growth of 90% strains of bacteria
 MBC : Minimum Bactericidal Concentration is the
lowest concentration of an antimicrobial required to
reduce the bacterial count
Spectrum : The range of bacteria against which the
antimicrobial agent can exert its effect. The
antibacterial agent may have
- Broad e.g. streptomycin, erythromycin
- Narrow e.g. tetracycline, chloramphenicol
Sensitivity: Susceptibility of the bacteria to get
injured by an antibacterial agent
Resistance: Ability of bacteria to grow even in the
presence of antibacterial
- Natural e.g. nalidixic acid not active against G+ve
- Acquired, generally due to change in DNA
 Antimicrobials - Classification
According to the types of microbes
against which they act
–  Antivirals (against viruses)
–  Antifungals (against fungi)
–  Antiprotozoals (against protozoa)
–  Antibacterials (against bacteria)
 Antibacterials – Classification
Based on the chemical structure

Group Examples Mode of Action

PENICILLINS (Beta lactam) Inhibit Bacterial
First Generation Penicillin G Cell wall
Second Cloxacillin synthesis-
Generation Dicloxacillin Bactericidal
Third Amoxycillin
Generation Ampicillin
Fourth Piperacillin
Generation Ticarcillin
CEPHALOSPORINS (Beta lactam) Inhibit
First Generation Cephalexin Bacterial
Cephadroxil Cell wall
Second Generation Cefaclor synthesis-
Cefuroxime Bactericidal
Third Generation Oral
Cefixime
Cefpodoxime
Cefdinir
Injection
Ceftazidime
Cefotaxime
Ceftriaxone
Fourth Generation Cefpirome
Cefipime
CLASSIFICATION OF PENICILLINS
GENER EXAMPLE SPECTRUM CHARACTERS
ATION
First Penicillin G Gram positive Not active orally,
susceptible to beta
lactamases
Second Cloxacillin Gram positive Active orally,
Dicloxacillin stable to beta
lactamases of gm
positive bacteria
Third Ampicillin, Gram positive & Active orally,
Amoxycillin Gm negative (Broad susceptible to beta
Spectrum lactamases
Penicillins)
Fourth Piperacillin Gram-positive and Not active orally,
Ticarcillin Gram negative susceptible to beta
including lactamases
Pseudomonas
(Extended Spectrum
Penicillins)
CLASSIFICATION OF CEPHALOSPORINS
GENER EXAMPLES USEFUL SPECTRUM
ATION
First Cefazolin, Streptococci except for
Cephalothin, penicillin-resistant strains,
Cephalexin Staphylococcus aureus except
for methicillin-resistant strains
Second Cefuroxime, Escherichia coli, Klebsiella,
Cefaclor, Proteus, Haemophilus
Cefoxitin, influenzae, Moraxella
Cefotetan catarrhalis. Not as active
against gram-positive organisms
as first-generation agents.
Inferior activity against S.
aureus compared to cefuroxime
but with added activity against
Bacteroides fragilis and other
Bacteroides spp.
 GENE EXAMPLES USEFUL SPECTRUM
RATION
Third Enterobacteriaceae,
Cefixime, Pseudomonas
Cefpodoxime, aeruginosa
Cefotaxime, (Ceftazidime only),
Ceftriaxone Serratia; Neisseria
Ceftazidime gonorrhoeae; activity
for S. aureus
Streptococcus
penumoniae and
Streptococcus pyogenesf
comparable to first-
agents. Activity against
Bacteroids spp. inferior
to that of cefoxitin and
cefotetan.
Fourth Cefepime Comparable to third-
Cefpirome generation but more
resistant to some -
lactamases.
 Beta- lactam antibiotics ( Penicillin
and Cephalosporin)
 
• Beta-lactam antibiotics interfere with cell wall synthesis
of the bacteria.

• Beta-lactam antibiotics penetrate the cell wall pores

called ‘porins’ to reach the periplasmic space.

• The space between the cell wall and cell membrane in

gram-positive bacteria is called ‘ periplasmic’ space.
• The gram-negative bacteria also possess an outer
membrane; therefore the space between cell wall and
inner menbrane in gram-negative bacteria is called
periplasmic space.
Periplasmic space
 PBP ( Penicillin binding protien)
• Specific proteins (enzyme) found on the surface of
the bacterial cell membrane.

• Are group of proteins characterized by affinity for

binding of penicillin

• involved in last stages of peptidoglycan (cell wall)

synthesis by inhibiting transpeptidase enzyme

• Inhibition of PBP leads to irregularity of cell wall

leading to cell death

• There are six different types of PBP’s eg: 1a, 1b,

1c, 2a
Antibiotic action on Penicillin binding protein
TYPE Function
-responsible for cell wall
synthesis
PBP Ib -responsible for the cross-
linking of the
peptidoglycan strands
supplements the activity of
PBP Ia PBP Ib enzyme
helps maintain the rod
shape of the bacilli
PBP 2
involved in the formation of
septa that divide growing
PBP3 bacteria into individual
new cells
Inhibition of PBP causes
cell lysis (disintegration or
rupture ) and rapid death of the
cell
both PBP Ia and PBP Ib sites
can be expected to exhibit a
stronger bactericidal effect
formation of spherical shaped
cells; which can not function
normally and can not grow
and multiply.
the bacteria grow into long
filamentous form; but can not
function normally and can not
grow and multiply.
 Bacterial Resistance
• Bacterial resistance is ability of bacteria to
exist and grow even in the presence of an
antibacterial.
BACTERIAL RESISTANCE
RESISTANCE

Natural Acquired
Bacteria may be
Bacteria can develop
inherently resistant
resistance to antibiotics
to an antibiotic

Gene
Mutation
Transfer
Natural Bacterial Resistance
Right from the time of discovery of the antibiotic, the bacterium dose not respond to the
drug. E.g. Nalidixic acid was discovered in 1964. Since then, it is not active against gram
positive bacteria.

Acquired Resistance
• Bacteria acquire resistance against an antibacterial, which other wise, was effective earlier.
This normally occurs due to change in their DNA.

Changes that results in bacterial resistance are of four types and include:
• a) Modification in the structure and/or number of the drug target site in the bacteria
• b) Changes in the bacterial cell membrane that decreases the ability of the drug to
penetrate the membrane (porin channels)
• c) Production of enzyme that degrade the antibiotic eg Beta-lactamase.
• d) Antibiotic efflux: pumps manufactured by the resistant bacteria cause efflux of
the antibiotics before they can act on their intracellular target sites.
 BETA-LACTAMASES AND
BACTERIAL RESISTANCE
 -Lactamases hydrolyze the amide bond in the -lactam
ring and prevent the active drug from reaching target
penicillin-binding proteins (PBPs).
• The majority of Gram-negative bacteria, staphylococci,
anaerobes and even mycobacteria produce -
lactamases.
• The most common -lactamases produced by
Enterobacteriaceae, and staphylococcal beta lactamases
are generally plasmid-mediated. These enzymes can be
effectively inhibited by -lactamase inhibitors unless the
latter are overwhelmed by -lactamase hyperproduction.
 STRUCTURE OF PENICILLIN
Side chain Β-lactam ring S

R-CH2CO NH-CH CH C(CH3)2

C N CHCOO-Na
Amidase O
Thiazolidine ring
Penicillinase/Betalactamase
 Hydrolysis of the beta lactam ring by
beta lactamase
Β-lactam ring S
destroyed
R-CH2CO NH-CH CH C(CH3)2

C N CHCOO-Na
O OH
Thiazolidine ring
Penicillinase/Betalactamase
 Types of Beta Lactamases:

The beta lactamases are mainly classified according to

their origin.

1.Chromosomally mediated: resistance controlled by the

chromosome.

2.Plasmid mediated: resistance controlled by plasmids.

Plasmid is a small piece of DNA, which can be transferred
from one bacterial cell to another easily. Plasmid can
replicate independently from the chromosomes and can be
transmitted to other bacteria of the same or different
species. 
 Bacterial Resistance
TRANSFERABLE CHROMOSOMAL
(OFTEN PLASMID MEDIATED)

i. Hydrolyze Penicillins & i. Predominantly hydrolyze

Cephalosporins either Penicillin or
Cephalosporin

ii.Produced in high ii.Usually in low concentration

concentration
iii. Shared among bacterial iii.Not shared among bacterial
species species – but tend to be specific
species.
 B-lactamase
These were separated into penicillinase (active
against penicillins) and cephalosporinase
(active against cephalosporins).
B-lactamase classified into six different types.
1. B-lactamase type I
2. B-lactamase type II
3. B-lactamase type III (including subgroups like
TEM, SHV, Amp C enzymes) found in gram
negative bacteria .
4. B-lactamase type IV
5. B-lactamase type V
6. B-lactamase type VI
 B-Lactamase types

Type Mediated by Developes resistance

against
I Chromosomal Cephalosporins

II Chromosomal Penicillins

III Plasmid Both

IV Chromosomal Both

V Plasmid Penicillins
EXTENDED SPECTRUM BETA LACTAMASES (ESBL):

• The extended spectrum beta lactamases are plasmid mediated enzymes

capable of inactivating a wide variety of beta lactams, including the third
generation cephalosporins, and penicillins.

• These enzymes have developed due to mutations in the commonly occurring

beta lactamases.

• ESBL are frequently resistant to many other classes of antibiotics like

aminoglycosides, and fluoroquinolones.

INHIBITION OF BETA-LACTAMASE

i) Either by having “enzyme-stable” antibiotics. E.g. Cloxacillin, Dicloxacillin,

methicillin.

ii) By using “Beta-lactamases inhibitors”

Clavulanic acid, Sulbactam, Tazobactam
AMINO Amikacin Inhibit Protein
GLYCOSIDES Neomycin synthesis -
Gentamycin Bactericidal
Tobramycin

MACROLIDES Erythromycin Inhibit Protein

Roxithromycin synthesis -
Azithromycin Bacteriostatic
Clarithromycin
TETRACYCLINE Doxicycline Inhibit Protein
Minocycline synthesis –
Bactericidal

CHLORAMPHENICOL Inhibit protein

synthesis
-Bactericidal
QUINOLONES
First Generation Nalidixic Acid
Second Norfloxacin Inhibit
Generation Ciprofloxacin DNA
Ofloxacin gyrase
enzyme-
Bactericidal
Third Generation Sparfloxacin
Levofloxacin
Gatifloxacin
Moxifloxcin
Fourth Generation Trovafloxacin
Gemifloxacillin
CLASSIFICATION OF QUINOLONES
GENERATION AGENTS ANTIMICROBIAL
SPECTRUM
Nalidixic acid Gram negative
First organisms (but not
generation pseudomonas
species).
Norfloxacin, Gram negative
Ciprofloxacin organisms (including
Ofloxacin, pseudomonas
species), gram
Lomefloxacin,
positive organisms
Second Pefloxacin (including
generation staphylococcus
aureus but not
Streptoccus
pneumonae, and
some atypical
pathogens).
GENERATION AGENTS ANTIMICROBIAL
SPECTRUM
Levofloxacin, Same for second
Sparfloxacin, generation agents
Moxifloxacin, plus expanded gram
Third
Gatifloxacin positive coverage
generation
and expanded
activity against
atypical pathogens.
Trovafloxacin Same as for third
Fourth generation agents
generation plus broad anerobic
coverage.
 Mode of action of fluoroquinolones
Fluoroquinolones act by inhibiting Topoisomerase
enzyme and act as bactericidal.
Topoisomerase

Type I Type II

DNA gyrase Topoisomerase IV

(Gram -ve) (Gram +ve)
DNA gyrase and topoisomerase both are present in both types of bacteria but
DNA gyrase is more predominant in Gram negative and Topoisomerase IV is
predominant in Gram positive bacteria
Mechanism of action contd….
DNA gyrase for supercoiling

Topoisomerase-IV
for relaxation &
separation of daughter DNA
MECHANISM OF ACTION OF
ANTIMICROBIAL DRUGS :
 MECHANISM OF ACTION OF
ANTIMICROBIAL DRUGS :
Interference with cell wall synthesis
Penicillins, Cephalosporins, Bacitracin, Vancomycin, and Cycloserine.

Damage to the cytoplasmic membrane

Polymixins, Colistin, Polyene antibiotics and Detergents.

Inhibition of protein synthesis and impairment of function of the

ribosomes
Aminoglycosides, Tetracyclines, Chloramphenicol, Macrolide antibiotics and
Lincomycin.

Interference with transcription/translation of genetic information

Quinolones, Metronidazole, Rifampicin and Ethambutol.

Antimetabolite action
Sulfonamides, Sulfones, PAS and Trimethoprim.
 Antianerobic and antiprotozoal drugs

Synthetic Nitro-immidazole derivatives

destroys DNA of
Metronidazole anaerobes and
protozoa
Tinidazole

Secnidazole

Ornidazole