LECTURES IN
MICROBIOLOGY
Antimicrobial Agents
LESSON 8
Sofronio Agustin
Professor
Lesson 8 Topics
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Antimicrobial Therapy
Selective Toxicity
Survey of Antimicrobial Agents
Microbial Drug Resistance
Drug-Host Interaction
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The Ideal Antimicrobial Drug
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Selective Toxicity
An ideal in chemotherapy that an
antimicrobial drug kills only pathogenic
microbes without harming the host.
Historically, reminiscent of the “magic
bullet” of Paul Ehrlich.
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Terms in Chemotherapy
Chemotherapy - use of drugs to treat
diseases.
Antimicrobials - any drug used in treating
infectious diseases.
Antibiotics - substances produced by some
microbes that inhibit or kill other microbes.
Synthetic drugs - antimicrobial compounds
synthesized in the laboratory.
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Historical Note in Chemotherapy
1928 – Alexander
Fleming discovered
penicillin from
Penicillium notatum.
1940 – Howard
Florey and Ernst
Chain performed first
clinical trials of
penicillin.
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Antibiotics
Naturally occurring
Metabolic products of bacteria and fungi
Reduce competition for nutrients and space
Examples:
Bacteria- Streptomyces, Bacillus
Molds -Penicillium, Cephalosporium
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Antimicrobial Activity
Narrow-spectrum
Broad-spectrum
Bactericidal
Bacteriostatic
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Antimicrobial Activity
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Modes of Action
Primary target sites of antimicrobial drugs in bacterial cells.
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Cell Wall Active Agents
 Bactericidal
 Penicillin and Cephalosporins – binds and blocks
peptidases involved in cross-linking the glycan
molecules.
 Vancomycin – prevents peptidoglycan elongation
 Cycloserine – inhibits the formation of the basic
peptidoglycan subunits
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Cell Wall Active Agents
Antibiotics weaken the cell wall and cause the cell to lyse.
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Cell Wall Active Agents
Penicillins and cephalosporins destroy the peptidoglycan
layer by disrupting the peptide cross bridges.
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Cell Wall Active Agents
Penicillin
 Natural penicillins
 Semi-synthetic penicillins
 Molecular Structure
 Thiazolidine ring
 Beta-lactam ring
 Variable side chain (R group)
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Penicillins
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Penicillinase
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Penicillins
Penicillinase-resistant penicillins
Extended-spectrum penicillins
Penicillins + -lactamase inhibitors
Carbapenems
Monobactam
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Penicillins
Bactericidal
Narrow spectrum.
Used to treat:
Streptococcal
Staphylococcal
Meningococcal, and
Spirochaete infections.
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Cephalosporins
Derived from
Cephalosporium
acremonium
Beta lactam antibiotic
like penicillin
Main ring different
from penicillin
2 sites for R groups
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Cephalosporins
Inhibit cell wall synthesis
Broad-spectrum or extended spectrum
antibiotic
2nd, 3rd, 4th generations more effective
against Gram-negatives
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Cephalosporins
Different R groups allow for versatility and improved
effectiveness of cephalosporins.
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Polypeptide Antibiotics
Bacitracin
Topical application
Effective against Gram-positives
Vancomycin
Glycopeptide
Important "last line" against
antibiotic resistant S. aureus
Hinders peptidoglycan elongation
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Mycolic Acid Inhibitors
Antimycobacterial antibiotics
Isoniazid (INH) - inhibits mycolic acid
synthesis
Ethambutol - inhibits incorporation of
mycolic acid into cell wall
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Inhibition of Protein Synthesis
Various antibiotics and their sites of protein synthesis
inhibition on the prokaryotic ribosome.
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Inhibitors of Protein Synthesis
Aminoglycosides
Broad-spectrum antibiotics
Changes shape of 30S subunit
Treatment of bubonic plague,STD, and
Gram-negative infections
Examples: Streptomycin, neomycin,
gentamycin
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Aminoglycoside Structure
Amino sugars and a six-carbon ring (aminocyclitol) in Streptomycin.
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Streptomyces
Streptomyces sp.
synthesizes many
antibiotics such
as:
aminoglycosides,
tetracycline,
chloramphenicol,
and erythromycin.
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Tetracycline
Broad spectrum
Interferes with tRNA
attachment
Treat intracellular
infections
Chemical Structure of Tetracycline
Risk to pregnant
women
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Chloramphenicol
Broad-spectrum
Binds 50S subunit,
inhibits peptide
bond formation
Cheap synthetic
Nitrobenzene ring of chloramphenicol
Treat typhoid fever
Side effects: Aplastic
anemia
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Erythromycin
A macrolide
Bactericidal
Binds 50s, prevents
translocation
Gram positives
Lactone ring of erythromycin
Side effects:
GI disturbance
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Streptogramins
A combination drug of quinopristin
and dalfopristin
Bactericidal
Binds 50s, inhibits translation
Affect Gram-positives
Example: Synercid
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Oxazolidinones
Bactericidal
Binds 50S, prevents formation of 70S
ribosome
Affect Gram-positives
Example: Linezolid
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Injury to Cell Membrane
Polymyxins
Interact with membrane phospholipids
Topical
Combined with Bacitracin and Neomycin as
over-the counter antibiotic
Amphotericin B
Anit-fungal agent
Forms complexes with sterols in the membrane
Causes cytoplasmic leakage
Can affect human cell membranes (toxicity)
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Nucleic Acid Synthesis Inhibitors
Rifamycin
Inhibits RNA synthesis
Anti-tuberculosis drug
Quinolones and fluoroquinolones
inhibits DNA unwinding enzymes
(gyrases)
Urinary tract infections
Ciprofloxacin
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Nucleic Acid Synthesis Inhibitors
Chloroquine
binds and cross-links the double helix
anti-malarial
Quinolones - e.g. Cirpofloxacin
inhibits DNA unwinding enzymes
(gyrases)
Azidothymidine (AZT)
Antiviral
Analogs of purines and pyrimidines
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Sulfa Drugs
 Analogs of important metabolites
(folic acid)
 Competitive enzyme inhibition
 Prevents the metabolism of
DNA, RNA, and amino acid
 Examples: Sulfonamides, and
trimethoprim
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Sulfa Drugs
Sulfonamides compete
with PABA for the active
site on the enzyme.
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Sulfonamides
Attachment of
different R groups
to the main
structural nucleus
affords versatility
of sulfonamides.
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Sulfonamides
Synthetic drug derived from dyes
(Prontosil of Domagk)
Synergistic combination as
Trimethoprim/Sulfamethoxazole
Treatment of pneumonia in AIDS
patients
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Antifungal Drugs
(a) Polyenes (b) Azoles (c) Fluorocytosine
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Antifungal Drugs
Amphotericin B
Polyene derivative
Affects sterols in fungal membrane
Causes cytoplasmic leakage
Can affect human cell membranes
(nephrotoxicity)
For systemic fungal infections
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Antifungal Drugs
Azoles- Miconazole, Triazoles
Inhibit ergosterol synthesis
For cutaneous fungal infections
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Antifungal Drugs
Echinocandins
Inhibit synthesis of -glucan, cell
wall component in yeasts
Used against Candida and
Pneumocystis infections
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Antifungal Drugs
Fluorocytosine (5-FC)
Cytosine analog, interferes with
RNA synthesis
Used in serious systemic fungal
infections
For Amphotericin B resistant fungi
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Antifungal Drugs
Pentamidine isothionate
May bind DNA
For Pneumocystis infections
Griseofulvin
Inhibition of microtubules (mitosis)
For superficial mycoses
Tolnaftate
Action unknown
For Athlete’s foot
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Antiprotozoal Drugs
Chloroquine
Inhibits DNA synthesis
For Malaria
Metronidazole
Damages DNA
For Entamoeba, Trichomonas infections
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Antihelminthic Drugs
Niclosamide
Prevents ATP generation
For Tapeworms
Praziquantel
Alters membrane permeability
For Flatworms
Pyrantel pamoate
Neuromuscular block
Intestinal roundworms
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Antihelminthic Drugs
Mebendazole
Inhibits nutrient absorption
For intestinal roundworms
Ivermectin
Paralyzes worm
For intestinal roundworms
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Antiviral Drugs
Few antiviral drugs available
Selective toxicity difficult - viruses are
intracellular in host cells
Targets in viral replication cycle:
-Entry
-Nucleic acid synthesis
-Assembly and release
Interferons – natural or artificial
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Antiviral Drugs
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Antiviral Drugs
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Antiviral Drugs
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Antiviral Drugs
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Antimicrobial Agents
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Antimicrobial Agents
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Antimicrobial Agents
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Antimicrobial Therapy
Identify infectious agent
Susceptibility testing
Minimum Inhibitory Concentration (MIC)
Minimum Bactericidal Concentration
(MBC)
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Kirby-Bauer Test
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Kirby-Bauer Test
The Kirby-Bauer Test is used to determine the effectiveness
of a drug by measuring the zone of inhibition.
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E-Test
The E-test as an alternative method to the Kirby-Bauer test
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Dilution Methods
The dilution test
determines actual MIC
values.
Correlated with in vivo
reactions
More accurate and
standardized
Modern micro-dilution
techniques are used in
automated methods.
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MIC
Comparative MIC values for sample bacterial isolates
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Combination Therapy
Synergism occurs when the effect of two
drugs together is greater than the
effect of either alone.
Antagonism occurs when the effect of two
drugs together is less than the effect
of either alone.
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Synergism
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Drug-Host Interaction
Toxicity to organs
Allergic reactions
Suppression or alteration of
microbiota
Effective drugs
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Drug-Induced Side Effects
Tetracycline treatments can cause teeth discoloration
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Disruption of Microbiota
Disrupting the microbiota in the intestine can result in superinfections
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Drug Toxicity
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Antimicrobial Resistance
 A variety of mutations can lead to antibiotic
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resistance.
Mechanisms of antibiotic resistance
1. Enzymatic destruction of drug
2. Prevention of penetration of drug
3. Alteration of drug's target site
4. Rapid ejection of the drug
Resistance genes are often on plasmids or
transposons that can be transferred between
bacteria.
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Antimicrobial Resistance
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Antimicrobial Resistance
Intermicrobial transfer of plasmids bearing resistance genes R
factors) by conjugation, transformation, and transduction.
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Natural Selection
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Antimicrobial Resistance
Misuse of antibiotics selects for resistance mutants.
Misuse includes:
 Using outdated, weakened antibiotics
 Using antibiotics for the common cold and
other inappropriate conditions
 Use of antibiotics in animal feed
 Failure to complete the prescribed regimen
 Using someone else's leftover prescription
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New Approaches
To counter emergence of drug resistance
requires new approaches to drug
development.
Prevent iron –scavenging
capabilities of microbes
Inhibit genetic controls (riboswitches)
Probiotics and prebiotics
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Future Approaches
Antimicrobial peptides- broad spectrum
antibiotics from plants and animals
Squalamine (sharks)
Protegrin (pigs)
Magainin (frogs)
Antisense agents -complementary DNA or
peptide nucleic acids that binds to a
pathogen's virulence gene(s) and
prevents transcription
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