Drugs, Microbes, Host –
The Elements of Chemotherapy
Antibiotics - Still Miracle
Drugs
Historical Perspective
• 100 years ago- 1 in 3 children died
of infectious disease before age 5
• Germ theory of disease
• Koch’s postulates
• Robert Ehrlich- microbe specific
dyes
• Sir Alexander Flemming-discovered
penicillin (1928)
Paul Ehrlich’s Magic Bullets
Salvarsan No. 606
Plate of Staphylococcus aureus inhibited
by Penicillium notatum
Fleming and Penicillin
Antibiotics
Topics
- Antimicrobial Chemotherapy
- Selective Toxicity
- Survey of Antimicrobial Drugs
- Microbial Drug Resistance
- Drug and Host Interaction
Antibiotics
• Naturally occurring antimicrobials
– Metabolic products of bacteria and fungi
– Reduce competition for nutrients and
space
• Bacteria that produce them:
– Streptomyces, Bacillus,
• Molds
– Penicillium, Cephalosporium
Selective Toxicity
• Drugs that specifically target
microbial processes, and not the
human host cellular processes.
Selective Toxicity
Mechanisms and sites
• Mechanism of action
–Bacterial cell wall
–Nucleic acid synthesis
–Protein synthesis
–Cell membrane
–Folic acid synthesis
Cell wall synthesis
Bactericidal
– Penicillin and cephalosporins – binds
and blocks peptidases involved in
cross-linking the glycan molecules
– Vancomycin – hinders peptidoglycan
elongation
– Cycloserine – inhibits the formation of
the basic peptidoglycan subunits
Antibiotics weaken the cell wall, and cause the cell to lyse.
The mechanism of action of penicillins and cephalosporins.
Penicillin
• Penicillin chrysogenum
• A diverse group (1st, 2nd , 3rd generations)
– Natural (penicillin G and V)
– Semisynthetic (Ampicillin, Carbenicillin)
• Structure
– Thiazolidine ring
– Beta-lactam ring
– Variable side chain (R group)
Chemical structure of penicillins
The R group is
responsible for
the activity of the
drug, and
cleavage of the
beta-lactam ring
will render the
drug inactive.
Penicillinase (b Lactamase)
Cephalosporin
• Cephalosporium acremonium (mold)
• Widely administered today
– Diverse group (natural and semisynthetic)
– 1st, 2nd, and 3rd generations
• Structure
– similar to penicillin except
• Main ring is different
• Two sites for R groups
The structure
of cephalosporins
The different
R groups
allow for
versatility
and improved
effectiveness.
Inhibition of Protein synthesis
• Aminoglycosides
– Bind to the 30S ribosome
– Causes Misreading of mRNA
• Tetracyclines
– Block attachment of tRNA
• Chloramphenicol
– Binds to the 50S ribosome
– Prevents peptide bond
formation
Inhibitors of Protein Synthesis
• Broad spectrum, toxicity problems
• Examples
– Aminoglycosides: Streptomycin,
neomycin, gentamycin
– Tetracyclines
– Macrolides: Erythromycin
– Chloramphenicol
Aminoglycosides
• From Streptomyces
• Inhibit protein synthesis
Streptomyces synthesizes
many different antibiotics
such as aminoglycosides,
tetracycline, chloramphenicol,
and erythromycin.
Tetracycline
• Inhibits proteins synthesis
• Broad spectrum and low cost
• Commonly used to treat sexually
transmitted diseases
• Minor side effect – gastrointestinal
disruption
Erythromycin
• Inhibits protein synthesis
• Broad-spectrum
• Commonly used as prophylactic
drug prior to surgery
• Side effects - low toxicity
Chloramphenicol
• Inhibits protein synthesis
• Broad-spectrum
• Treat typhoid fever, brain
abscesses
• Rarely used now due to side effects
– aplastic anemia
Aminoglycoside
Sites of inhibition on the procaryotic ribosome
Injury to the Plasma Membrane
• Polymyxin B (Gram negatives)
– Topical
– Combined with bacitracin and neomycin
(broad spectrum) in over-the-counter
preparation
Inhibitors of Nucleic Acid
Synthesis
• Rifamycin
– Inhibits RNA synthesis
– Antituberculosis
• Quinolones and fluoroquinolones
– Ciprofloxacin
– Inhibits DNA gyrase
– Urinary tract infections
Folic acid synthesis
Sulfonamides (sulfa drug) and
trimethoprim
– Analogs
– Competitive inhibition of enzymes
– Prevents the metabolism of DNA,
RNA, and amino acid
Sulfonamides compete with PABA for the
active site on the enzyme.
The sulfonamide Sulfamethoxazole
is commonly used in combination
with trimethoprim
Antiviral
• Increasing types of drugs becoming available
• However, it is difficult to maintain selective
toxicity
• Effective drugs – target viral replication cycle
– Entry
– Nucleic acid synthesis
– Assembly/release
• Interferon – genetically engineered antiviral
protein from a human gene
Antiviral drug structures and their unique
modes of action.
Antiviral drug structures and their unique
modes of action.
Antiviral drug structures and their unique
modes of action.
Other types of antimicrobials
• Antifungal – ketoconizole
• Antiprotozoan – metronidazole
– Treat giardia
• Antimalarial – Quinine
– malaria
• Antihelminthic – mebendazole
– Tapeworms, roundworms
Mechanisms of Antibiotic
Resistance
• Enzymatic destruction of drug
• Prevention of penetration of drug
• Alteration of drug's target site
• Rapid ejection of the drug
Antimicrobial Resistance
• Relative or complete lack of
effect of antimicrobial against a
previously susceptible microbe
Antibiotic Resistance
Figure 20.20
Antibiotic Resistance
Intermicrobial transfer of plasmids containing resistance genes (R factors)
occurs by conjugation, transformation,and transduction
Figure 20.20
What Factors Promote
Antimicrobial Resistance?
• Exposure to sub-optimal levels of
antimicrobial
• Inappropriate use
• Exposure to microbes carrying
resistance genes
Inappropriate Antimicrobial Use
• Prescription not taken correctly
• Antibiotics for viral infections
• Antibiotics sold without
medical supervision
• Spread of resistant microbes
in hospitals due to lack of hygiene
Inappropriate Antimicrobial Use
• Inadequate surveillance or defective
susceptibility assays
• Poverty or war
• Use of antibiotics in foods
• Lack of quality control in manufacture or
outdated antimicrobial
Antibiotics in Foods
• Antibiotics are used in animal feeds and
sprayed on plants to prevent infection
and promote growth
• Multi drug-resistant Salmonella typhi
has been found in 4 states in 18 people
who ate beef fed antibiotics
Antibiotic Drug and Host Interaction
• Toxicity to organs
• Allergic reactions
• Suppress/alter microflora
• Effective drugs
Tetracycline treatments
can cause teeth discoloration.
Disrupting the normal flora in the intestine can result in
superinfections.
Finding an effective drug for
trreatment
• Identify infectious agent
• Perform sensitivity testing
• Often the Minimum Inhibitory
Concentration (MIC) is determined
The Kirby-Bauer Test.
Sensitivity test such as the Kirby-Bauer Test can be used to
determine the effectiveness of a drug by measuring the zone of
inhibition.
Consequences of
Antimicrobial Resistance
• Infections
resistant to
available
antibiotics
• Increased cost
of treatment
Multi-Drug Resistant TB
Proposals to Combat
Antimicrobial Resistance
• Speed development of new antibiotics
• Track resistance data nationwide
• Restrict antimicrobial use
• Direct observed dosing (TB)
Proposals to Combat
Antimicrobial Resistance
• Use more narrow spectrum
antibiotics
• Use antimicrobial cocktails
The Future of Chemotherapeutic
Agents
Antimicrobial peptides
– Broad spectrum antibiotics from
plants and animals
• Squalamine (sharks)
• Protegrin (pigs)
• Magainin (frogs)
The Future of Chemotherapeutic
Agents
Antisense agents
– Complementary DNA or peptide nucleic
acids that binds to a pathogen's virulence
gene(s) and prevents transcription