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 ( lactam ring)
• Natural penicillins
• Narrow range of action
• Susceptible to penicillinase (
lactamase)
Prokaryotic Cell Walls
Penicillins
Fig 20.6

Figure 20.6
Penicillinase ( Lactamase)

Figure 20.8
 Semisynthetic Penicillins

• Penicilinase-resistant penicillins
• Carbapenems: very broad
spectrum
• Monobactam: Gram negative
• Extended-spectrum penicillins
• Penicillins + -lactamase inhibitors
 Other Inhibitors of Cell Wall
Synthesis
• Cephalosporins
– 2nd, 3rd, and 4th
generations
more effective
against gram-
negatives

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 over-
the-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