Download Chapter 21 Antimicrobial medications

Chapter 21
Antimicrobial medications
Biology 261
Prof. Santos
Medgar Evers College
• Chemotherapeutic- a chemical used to
treat a disease
• Antimicrobial drug- a chemical used to
treat microbial infections
History and development
• 1- Paul Ehrlich developed Salvarsan to
treat syphilis in laboratory animals.
Discovery of Antibiotics
• In 1928, Alexander Fleming discovered that the
fungi Penicillium produces a chemical that kills
bacteria. He called this substance penicillin.
Features of Antimicrobial drugs
1- Made naturally by certain
microorganisms. Many come from
microorganisms that normally reside in
soil.
2- Commercially they can be made in large
numbers in a laboratory.
3- In a lab, they can be modified to alter their
chemical and physical characteristics.
• Antibiotics that have been chemically
altered are called semi-synthetic.
4- selective toxicity
• Useful antimicrobial drugs cause greater
harm to microorganisms than to the
human host. They do this by interfering
with essential biological structures or
pathways that are common in
microorganisms but not humans.
Therapeutic index
• The toxicity of a given drug is expressed
as its therapeutic index.
• A high therapeutic index means that the
drug is less toxic to a patient because the
drug acts on a biochemical process of
bacteria that is not found on humans.
• A drug with a low therapeutic index must
be carefully monitored in the patient’s
blood to ensure toxic levels are not reach.
5- antimicrobial action
Those drugs that inhibit bacterial growth are
called bacterio-static. These drugs depend
on the host’s natural immune system to
clear the pathogen from the body.
Sulfonamides, erythromycin, and
tetracyclines are examples of bacteriostatic drugs. Antibiotics that actually kill
bacteria are bacteriocidal.
Those drugs that kill bacteria are called
bactericidal.
6- Antimicrobial drugs that affect a wide
range of bacteria are called broad
spectrum antimicrobials.
These are important during life threatening
acute infections when there is no time to
culture and identify the agent of disease.
7- Antimicrobials that affect a limited range
of bacteria are called narrow-spectrum
antimicrobials.
8- Combining drugs to fight infection must
be carefully monitored. 3 situations to
know!
A- antagonistic
when one drug interferes with the action
of another.
B- synergistic
when one drug enhances the
effectiveness of another drug
C- Additive
When the effect is neither antagonistic or
synergistic
9- half-life
• The rate of elimination of a drug in the
body after it has been metabolize. The half
life is the time required for the body to
eliminate one half of the original
concentration in the serum.
• *Half life determines the size of dosage
and frequency of the dosage.
10- Adverse effects
Adverse effects include allergic reactions
to medications, toxic effects, and the
suppression of the normal flora.
11- Resistance to antimicrobial agents
include innate resistance (inherited) and
acquired through a mutation.
**members of the genus Mycoplasma lack a
cell wall so penicillin does not affect it.
Mechanisms of action of
antimicrobial drugs
1- inhibit cell wall synthesis
2- inhibit protein synthesis
3- inhibit nucleic acid synthesis
4- inhibit metabolic pathways
5- inhibit cell membrane integrity
6- special drugs used against
Mycobacterium tuberculosis
Cell wall synthesis
• Antimicrobial drugs that inhibit cell wall
synthesis include the penicillins,
cephalosporins, and other beta lactam
drugs.
• The beta lactam drugs include penicillin,
cephalosporin, monobactam, and carbapenem.
• They all share a chemical structure called a beta
lactam ring.
• The beta lactam drugs competitively inhibit a
group of enzymes that catalyze formation of
peptide bridges between adjacent glycan
strands in the final stages of peptidoglycan
formation.
Antibacterial Drugs That Inhibit Cell Wall Synthesis
• Penicillins, Cephalosporins, other β-Lactam Drugs (cont…)
– Interfere with peptidoglycan
β-lactam drugs
Vancomycin
Competitively inhibit enzymes
Binds to the amino acid side
synthesis
that help form peptide bridges
chain of NAM molecules,
between adjacent glycan
blocking peptidoglycan
chains.
synthesis.
– Weaken cell walls, leads
to cell lysis
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Peptidoglycan
(cell wall)
Cytoplasmic
membrane
NAG
NAM
Bacitracin
Interferes with the transport
of peptidoglycan precursors
across the cytoplasmic
membrane.
• Antibacterial Drugs That Inhibit Cell Wall Synthesis
– Bacterial cell walls are unique, contain peptidoglycan
• Great target for drugs: often have high therapeutic index
• Penicillins, Cephalosporins, other β-Lactam Drugs
– All have β-Lactam ring
– Competitively inhibit enzymes that
catalyze formation of peptide
bridges between adjacent glycan
strands; disrupt cell wall synthesis
– Called penicillin-binding proteins
(PBPs) since bind penicillin
– Only effective against actively
growing cells
Antibacterial Drugs That Inhibit Cell
Wall Synthesis
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Basic Structure
Side Chain
C
•
C
CH2
The penicillins share basic structure
– Side chain modified to create derivatives
– Five general groups of penicillins
• Natural are from Penicillium chrysogenum
– Narrow-spectrum, act against Gram-positives and a few
Gram-negatives
• Penicillinase-resistant developed in response to S. aureus
strains
– Some now able to produce altered PBPs to which βlactam drugs do not bind (e.g., methicillin-resistant
S. aureus, or MRSA)
S
NH CH
C
CH
N
O
CH3
C
CH3
COOH
C
H
β-lactam ring
Penicillin G
OCH2
Penicillin V
(acid-resistant)
OCH3
Methicillin
(penicillinase-resistant)
OCH3
CI
N
CI
O
Dicloxacillin
(acid- and penicillinase-resistant)
CH3
Ampicillin
(broad-spectrum and acid-resistant)
CH
NH2
HO
Amoxicillin
(like ampicillin but more active
and requiring less frequent doses)
CH
NH2
CH
S
COONa
CH
NH
C O
O
N
N
O
C2 H5
Ticarcillin
(more activity against Gramnegative rods, including
Pseudomonas, but not as effective
against some Gram-positive
organisms)
Piperacillin
(like ticarcillin but a broader
spectrum of activity)
Antibacterial Drugs That Inhibit Cell
Wall Synthesis
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Basic Structure
Side Chain
C
•
C
CH2
The penicillins share basic structure
– Side chain modified to create derivatives
• Broad-spectrum act against Gram-positives and Gramnegatives due to modified side chain
– Inactivated by many β-lactamases
• Extended-spectrum have greater activity against
Pseudomonas species
– Reduced activity against Gram-positives; destroyed by
many
β-lactamases
• Penicillins + β-lactamase inhibitor includes inhibitor to
protect penicillin
S
NH CH
C
CH
N
O
CH3
C
CH3
COOH
C
H
β-lactam ring
Penicillin G
OCH2
Penicillin V
(acid-resistant)
OCH3
Methicillin
(penicillinase-resistant)
OCH3
CI
N
CI
O
Dicloxacillin
(acid- and penicillinase-resistant)
CH3
Ampicillin
(broad-spectrum and acid-resistant)
CH
NH2
HO
Amoxicillin
(like ampicillin but more active
and requiring less frequent doses)
CH
NH2
CH
S
COONa
CH
NH
C O
O
N
N
O
C2 H5
Ticarcillin
(more activity against Gramnegative rods, including
Pseudomonas, but not as effective
against some Gram-positive
organisms)
Piperacillin
(like ticarcillin but a broader
spectrum of activity)
The cephalosporins
• Contain the beta lactam ring!
• Are grouped into 1st, 2nd, 3rd ,and 4th
generation cephalosporins.
• They include cephalexin, cephradine,
ceflacor, cefibuten, and cefipime.
Other b- lactam antibiotics
• The carbapenems and monobactams are
very resistant to lactamases.
• Carbapenems are effective against both
gram + and gram – bacteria. They include
imipenem and meropenem.
• The only monobactam used
therapeutically is aztreonam. It is effective
against species of the Enterobacteriaceae
family.
Vancomycin
• Binds to the terminal amino acids of the
peptide chain of NAM molecules that are
being assembled to form glycan chains.
By doing so it blocks the production of
peptidoglycan. They do not cross the outer
membrane of gram – bacteria so they are
resistant. Vancomycin must be
administered intravenously.
Bacitracin
• These drugs interfere with cell wall
biosynthesis by interfering with the
transport of precursors across the
cytoplasmic membrane.
• They are only used as topical ointments
due to their toxicity.
Inhibiting protein synthesis
– All cells synthesize proteins
– Can exploit differences between prokaryotic and eukaryotic
ribosomes
• Prokaryotes have 70S, eukaryotes have 80S ribosomes
• Mitochondria also
have 70S ribosomes
Macrolides
Prevent the continuation
– May account for Streptogramins
of protein synthesis.
Each interferes with a
some toxicity
distinct step of protein
Chloramphenicol
synthesis.
Prevents peptide
of these drugs
bonds from being
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Lincosamides
Prevent the
continuation of
protein synthesis.
formed.
50S
30S
Tetracyclines and
glycylcyclines
Block the attachment
of tRNA to the ribosome.
Oxazolidinones
Interfere with the
initiation of protein
synthesis.
Aminoglycosides
Block the initiation of
translation and cause the
misreading of mRNA.
Drugs against nucleic acid
synthesis
1- the fluoroquinolones inhibit the enzyme
topoisomerase which helps maintain DNA
in a supercoil state.
2- the Rifamycins block prokaryotic RNA
Polymerase from initiating transcription.
Drugs against metabolic pathways
1- sulfonamides block the action of an
enzyme that normally binds to PABA, a
substrate in the folate pathway. They
closely resemble PABA, so the enzyme
binds to it and the entire pathway is
blocked.
2- trimethoprim
These drugs inhibit the bacterial enzyme
that catalyzes a metabolic step following
the one inhibited by sulfonamides.
Drugs that interfere with cell
membrane integrity
1- polymyxin alters the permeability of the
cell membrane leading to leakage and cell
damage.
2-Daptomycin inserts into the membrane
leading to cell damage and eventually
death.
Special medications against
Mycobacterium
1- first line drug such as Isoniazid inhibits
the synthesis of mycolic acid, an important
component of the cell wall.
2- Ethambutol inhibits enzymes used to
synthesize other cell wall components.
3- Rifampin, an antimicrobial drug used to
block the process of transcription by
blocking RNA Polymerase.
4- Ampicillin, a broad spectrum penicillin.