Lecture 02

Bio 319: Antibiotics
Lecture Two
Topic: Characteristics of antibiotics and their classification

Lecturer: Dr. G. Kattam Maiyoh

13/02/2013 GKM/BIO319:Antibiotics/Lec. 02/Sem02/2013 1

Brief overview
• General aspects
• Classification
– Cidal vs. Static
– Target organism
– Spectrum of activity
– Mechanism of action
• Cell synthesis inhibitors
– Beta lactams
» Penicillins
» cephalosporins

13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 2

General Aspects of antibiotics
• Principle:
Inhibit growth of bacteria without harming the host
– Drug must penetrate body tissue to reach bacteria (exception: GI
infection)
(unique targets: cell wall, protein synthesis, metabolic pathways…)
– Bacteria targeted must be within the spectrum of the Antibiotic
– Drug can be bactericidal or bacteriostatic
– Different agents can be combined for synergistic effect
(Note: not all combinations are useful, e.g. cell wall synthesis
inhibitors loose effectiveness when combined with bacteriostatic drugs)
– Identification of the invasive microorganism necessary for optimal
treatment
• General side effect:
Alteration in normal body flora
– GI tract harbors symbiotic bacteria which are killed by antibiotic =>
resistant bacteria repopulate the niche = secondary or superinfection
result
(most common: overgrowth of Clostridium difficile)

Classification of antibiotics
• At the highest level, antibiotics can be classified as
either bactericidal or bacteriostatic.
• Bactericidals kill bacteria directly while bacteriostatics
prevent cell division.
• However, these classifications are based on laboratory
behavior; in practice, both of these are capable of
ending a bacterial infection.
• The bactericidal activity of antibiotics may be growth
phase dependent and in most but not all cases action
of many bactericidal antibiotics requires ongoing cell
activity and cell division for the drugs' killing activity


a. Static vs. Cidal
•The graphs show the growth curves for a
bacterium treated with two drugs.

•The upper curve shows the activity of a
bacteriostatic drug.

•The bacterial growth resumes when the
drug is withdrawn. •
Penicillins, aminoglycoside, vanconmyci
•The cidal drug, shown in the lower n, bacitracin , the polymyxin, and colistin
are bactericidal.
graph, kills bacteria from the time of
administration to the culture. • Tetracyline , Fusidic acid
, Macrolides, Sulfonamides and sulfones
on the other hand, are bacteriostatic.


Classification of Antibiotics
• Bacteriostatic vs. Bactericidal


Target organism
• Another method - according to which
bacterial strains they affect:
• For example;
Staphylococcus,
Streptococcus, or
Escherichia coli,.


Spectrum of activity
May also be classified based on
spectrum of activity;
1. Broad spectrum
2. Narrow spectrum
3. Extended spectrum


Antibiotic Spectrum of Activity

• No antibiotic is effective against all
microbes

b. Based on action against the infecting organism


Classification: Mode of action
• Cell wall synthesis inhibitors • Injury to plasma membrane
– Beta-lactams -polymyxin B
(penicillins, cephalosporins, aztr - mystatin
eonam, imipenem) - amphotericin B
– Poly-peptides - miconazole
(bacitracin, vancomycin)
• Protein synthesis inhibitors
• Inhibition of njucleic acid
– Aminoglycosides
replication and transcription
– Tetracyclins
– Macrolides
- Quinolones
– Chloramphenicol - Rifampin
– Clindamycin
• Inhibitors of essential metabolites
(folate)
– Sulfonamides
– Trimethoprim


Inhibitors of Cell Wall Synthesis


Cell wall synthesis inhibitors
Bacterial cell wall:

Three types:
• Gram-negative (e.g. E.coli, Salmonella)
– Few peptidoglycan layers (Lipopolysaccheride)
• Gram-positive (e.g. Staphylococci, Listeria)
– Many peptidoglycan layers (Lipoteichoic acid)
– Stains w/ crystal-violet/iodine
• Acid-fast positive (Mycobacteria)
– Cell wall contains waxy substance (Mycolic acid)
– Stain w/ acid fast test (heating required)


• There are three types
– Gram-negative (e.g.
E.coli, Salmonella)
• Have few peptidoglycan layers
• (stain safranin or fuchsin)
– Gram-positive (e.g. E.coli,
Staphylococci, Listeria
• Have many peptidoglycan
layers
• stains with crystal violet
• typically lack the outer
membrane found in gram-
ve.
– Acid-fast Positive (Mycobacteria)
• Cell wall contains waxy
substance (Mycollic acid)
• Stains with acid fast (heating
required)


Antibiotics - Cell wall synthesis inhibitors

Beta-lactam antibiotics:
1928 - Alexander Fleming
observes the
antibacterial effects of
Penicillin
1940 - Florey and Chain
extract Penicillin


The beta lactams
• The β-lactam group of antibiotics includes an
enormous diversity of natural and semi-synthetic
compounds that inhibit several enzymes associated
with the final step of peptidoglycan synthesis.
• All of this enormous family are derived from a β -
lactam structure: a four-membered ring in which the β
-lactam bond resembles a peptide bond.
• The multitude of chemical modifications based on this
four-membered ring permits the astonishing array of
antibacterial and pharmacological properties within
this valuable family of antibiotics.


The Beta-Lactams

R – variable side chain

Monobactam nucleus


Penicillinase ( Lactamase)

More when we discuss antibiotic resistance

Figure 20.8

• Penicillium notatum produces the
only naturally occurring agent –
penicillin G or benzylpenicillin

• Penicillium chrysogenum produces
6-aminopenicillanic acid, raw
material for semi-synthetics


Targets for beta lactams
• The targets for β-lactam drugs are the penicillin binding
proteins (PBP's), so called because they bind radioactive
penicillin and can be detected by autoradiography of gels on
which bacterial proteins have been separated
electrophoretically.
• The penicillin binding proteins have transpeptidase or
carboxypeptidase activity and they act to regulate cell size and
shape.
• They are also involved in septum formation and cell division.
Bacteria have several individual penicillin binding proteins, each
with a separate function.
• Conventionally these are numbered according to size, with PBP
1 as the largest protein.
• The PBP 1 of one bacterium will not necessarily have the same
function as the PBP 1 of a different organism.


Target
• The β-lactam antibiotics also stimulate the activity of
autolysins.
• These are enzymes that are responsible for the natural
turnover of cell wall polymers to permit growth of the
cells.
• Under normal conditions, these enzymes produce
controlled weak points within the peptidoglycan
structure to allow for expansion of the cell wall
structure.
• This activity is stimulated by β-lactams, causing a
breakdown of peptidoglycan and leading to osmotic
fragility of the cell and ultimately to cell lysis.


Penicillins - classification
– Narrow spectrum – penicillinase sensitive
– Narrow spectrum – penicillinase resistant
– Broad spectrum penicillins
– Extended-spectrum penicillins
• Cephalosporines
• Carbapenems
• Monobactams
• Vancomycin, Bacitracin


Natural Penicillins
• Penicillin G, Penicillin V


Penicllins (general info.)
• Derived from the fungus Penicillium
• Attains therapeutic concentration in most
tissues
• However has poor CSF penetration
• Renal excretion
• Side effects:
hypersensitivity, nephritis, neruotoxicity, plate
let dysfunction


Penicillins
Inhibit transpeptidase required for cross-linking peptidoglycan
chains
Also inactivate an inhibitor of an autolytic bacterial enzyme => lysis
Narrow spectrum – penicillinase (= β-lactamase) sensitive
• Benzylpenicillin
– Naturally occuring
– Poor oral availability (sensitive to stomach acid)
=> given by injection
– Active against gram-positive bacteria
• Phenoxymethylpenicillin
– Better oral availability (acid resistant)


Narrow spectrum – penicillinase (= β-lactamase) resistant
• Methicillin
– Semisynthetic
– Poor oral availability (only parenteral)
– Active against gram-pos bacteria
– Mostly used for Staphylococcus aureus
• Oxacillin
– Good oral availability
• Cloxacillin
• Dicloxacillin


Broad spectrum – penicillinase (= β-
lactamase) sensitive
(Also referred to as Aminopenicillins)
• Ampicillin
– Semisynthetic
– Good oral availability
– Active against gram-pos and gram-neg bacteria
– Active against enterobacteria
• Amoxicillin
– Excellent oral availability

Extended spectrum – penicillinase (=
β-lactamase) sensitive
(Also called Carboxypenicillins)
• Carbenicillin
– Semisynthetic
– Poor oral availability
– Active against gram-pos and gram-neg bacteria
– Active against Pseudomonas aeruginosa, Klebsiella
• Ticarcillin
• Mezlocillin
• Pipercillin

Penicillins

Figure 20.6

Cephalosporines
Derived from Cephalosporium sp.
(same antibiotic mechanism as penicillins)
Cross-allergies with penicillins are common
Some CSs antagonize Vitamin K => leads to bleeding
Some CSs block alcohol oxidation => disulfiram effect ( read a bit)
Classified into generations:
• 1-4
• Increasing activity against gram-negative bacterial and
anaerobes
• Increasing resistance to destruction by beta-lactamases
• Increasing ability to reach cerebrospinal fluid


Cephalosporins
• The first cephalosporins - first generation while later, more
extended spectrum cephalosporins were classified as second
generation cephalosporins.
• Each newer generation has significantly greater gram-negative
antimicrobial properties than the preceding generation,
• Most cases with decreased activity against gram-positive
organisms.
• Fourth generation cephalosporins, however, have true broad
spectrum activity.


Cephalosporin structure

• Base molecule is 7-
aminocephalosporanic acid
produced by a Sardinian
sewer mold
• R groups determine
spectrum of activity and
pharmacological properties
• Mechanism of
action/resistance and class
pharmacology essentially
the same as penicillins


Will consider:
• Examples of each generation
• Effectiveness
• Absorption/Excretion
• Distribution
• Therapeutic uses
• Metabolism

Cefaclor structure – Member of
The 2nd generation cephalosporins

First Generation Cephalosporins

• Cefazolin, cephalexin, cephadro
xil
• Excellent against susceptible
staph and strep
• Modest activity against G -ve
• Cefazolin given
parentally, others orally
• More than half of the drug is
bound to plasma proteins
• Excreted by kidneys
unmetabolized
• Good for staph and strep skin
and soft tissue infections


Second Generation Cephalosporins
• Include;
– Cefaclor,
– cefuroxime,
– cefprozil
• Modest activity against G+, increased activity
against G-, works against anaerobes
• Cefaclor and cefprozil given orally
• Absorption and excretion same as first
generation.
• Good for treating respiratory tract
infections, intra-abdominal infections, pelvic
inflammatory disease, diabetic foot ulcers


Third Generation Cephalosporins
• Ceftaxime, ceftriaxzone, cefoperazon
e, cefpodoxime
• Broad spectrum killers
• Drugs of choice for serious
infections
• No effect against Listeria and beta-
lactamase producing pneumococci
• Cefpodoxime given orally, others
parentally
• Most excreted by kidney
• Therapeutic uses
– Bacterial meningitis (2
exceptions)
– Lyme disease
– Life-threatening G -ve sepsis
(infection)


Fourth Generation Cephalosporin

– e.g.Cefepime
– Same antimicrobial spectrum as third
generation but resists more beta-lactamases
– Given parentally, excellent penetration into
CSF
– Good for nosocomial infections


Toxicity/Contraindications
of Cephalosporins
• Hypersensitivity reactions (uncommon) essentially
same as for penicillins
• Cross-reaction between 2 classes


Lecture 02

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