Antimicrobial Drugs
Fading Miracle?
Ehrlich’s Magic Bullets
Fleming and Penicillin
Chemotherapy
• The use of drugs to treat a disease
• Selective toxicity: A drug that kills
harmful microbes without damaging
the host
Antibiotic/Antimicrobial
• Antibiotic: Chemical produced
by a microorganism that kills or
inhibits the growth of another
microorganism
• Antimicrobial agent: Chemical
that kills or inhibits the growth of
microorganisms
Microbial
Sources
of
Antibiotics
Antibiotic Spectrum of Activity
• No antibiotic is effective against all
microbes
Mechanisms of
Antimicrobial Action
• Bacteria have their own enzymes
for
–Cell wall formation
–Protein synthesis
–DNA replication
–RNA synthesis
–Synthesis of essential
metabolites
Mechanisms of
Antimicrobial Action
• Viruses use host enzymes inside
host cells
• Fungi and protozoa have own
eukaryotic enzymes
• The more similar the pathogen and
host enzymes, the more side
effects the antimicrobials will have
Modes of Antimicrobial Action
Antibacterial Antibiotics
Inhibitors of Cell Wall Synthesis
• Penicillin (over 50 compounds)
–Share 4-sided ring (b lactam ring)
• Natural penicillins
• Narrow range of action
• Susceptible to penicillinase (b
lactamase)
Prokaryotic Cell Walls
Penicillins
Fig 20.6
Figure 20.6
Penicillinase (b Lactamase)
Figure 20.8
Semisynthetic Penicillins
• Penicilinase-resistant penicillins
• Carbapenems: very broad
spectrum
• Monobactam: Gram negative
• Extended-spectrum penicillins
• Penicillins + b-lactamase inhibitors
Other Inhibitors of Cell Wall
Synthesis
• Cephalosporins
–2nd, 3rd, and
4th
generations
more effective
against gramnegatives
Figure 20.9
Other Inhibitors of Cell Wall
Synthesis
• Polypeptide antibiotics
–Bacitracin
• Topical application
• Against gram-positives
–Vancomycin
• Glycopeptide
• Important "last line" against
antibiotic resistant S. aureus
Other Inhibitors of Cell Wall
Synthesis
• Antibiotics
effective against
Mycobacteria:
interfere with
mycolic acid
synthesis or
incorporation
– Isoniazid (INH)
– Ethambutol
Inhibitors of Protein Synthesis
• Broad spectrum, toxicity problems
• Examples
– Chloramphenicol (bone marrow)
– Aminoglycosides: Streptomycin,
neomycin, gentamycin (hearing, kidneys)
– Tetracyclines (Rickettsias & Chlamydia;
GI tract)
– Macrolides: Erythromycin (gram +, used
in children)
Injury to the Plasma Membrane
• Polymyxin B (Gram negatives)
–Topical
–Combined with bacitracin and
neomycin (broad spectrum) in overthe-counter preparation
Inhibitors of Nucleic Acid
Synthesis
• Rifamycin
–Inhibits RNA synthesis
–Antituberculosis
• Quinolones and fluoroquinolones
–Ciprofloxacin
–Inhibits DNA gyrase
–Urinary tract infections
Competitive Inhibitors
–Sulfonamides (Sulfa drugs)
• Inhibit folic acid synthesis
• Broad spectrum
Figure 5.7
Antifungal Drugs
• Fungi are
eukaryotes
• Have unique
sterols in their cell
walls
• Pathogenic fungi
are often outside
the body
Antiviral Drugs
• Viruses are composed of nucleic
acid, protein capsid, and host
membrane containing virus proteins
• Viruses live inside host cells and
use many host enzymes
• Some viruses have unique
enzymes for DNA/RNA synthesis or
protein cutting in virus assembly
Figure 20.16a
Antiviral Drugs
Nucleoside and Nucleotide Analogs
Figure 20.16a
Analogs Block DNA Synthesis
Figure 20.16b, c
Antiviral Drugs
Enzyme Inhibitors
• Inhibit assembly
–Indinavir (HIV)
• Inhibit attachment
–Zanamivir (Influenza)
• Inhibit uncoating
–Amantadine (Influenza)
Antiviral Drugs
Enzyme Inhibitors
• Interferons prevent spread of viruses
to new cells (Viral hepatitis)
• Natural products of the immune
system in viral infections
Antiprotozoan Drugs
• Protozoa are
eukaryotic cells
• Many drugs are
experimental and
their mode of
action is unknown
Antihelminthic Drugs
• Helminths are
macroscopic
multicellular
eukaryotic
organisms:
tapeworms,
roundworms,
pinworms,
hookworms
Antihelminthic Drugs
• Prevent ATP generation (Tapeworms)
• Alters membrane permeability
(Flatworms)
• Neuromuscular block (Intestinal
roundworms)
• Inhibits nutrient absorption (Intestinal
roundworms)
• Paralyzes worm (Intestinal
roundworms)
Measuring Antimicrobial
Sensitivity
• E Test
• MIC: Minimal
inhibitory
concentration
Measuring Antimicrobial
Sensitivity: Disk Diffusion
Antibiotic Resistance
Figure 20.20
Antimicrobial Resistance
• Relative or complete lack of
effect of antimicrobial against a
previously susceptible microbe
• Increase in MIC
Mechanisms of Antibiotic
Resistance
• Enzymatic destruction
of drug
• Prevention of
penetration of drug
• Alteration of antibiotic
or target site
• Rapid ejection of the
drug
Antibiotic Selection for
Resistant Bacteria
What Factors Promote
Antimicrobial Resistance?
• Exposure to sub-optimal levels
of antimicrobial
• 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
• Lack of quality control in
manufacture or outdated
antimicrobial
• Inadequate surveillance or
defective susceptibility assays
• Poverty or war
• Use of antibiotics in foods
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
Consequences of
Antimicrobial Resistance
• Infections
resistant to
available
antibiotics
• Increased
cost of
treatment
Multi-Drug Resistant TB
MRSA “mer-sah”
• Methicillin-Resistant
Staphylococcus aureus
• Most frequent nosocomial
(hospital-acquired) pathogen
• Usually resistant to several
other antibiotics
Vancomycin Resistant Enterococci
Vancomycin Use USA
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