Chapter 20: Antimicrobial Drugs

ANTIMICROBIAL DRUGS
Chemotherapy: treatment with chemical
substances
Antibiotic: substance produced by
microorganism that, in small quantities,
inhibits another microorganism*
Spectrum of activity: range of different
microbes affected by an antibiotic

*Entirely synthetic drugs are technically

“antimicrobial drugs” rather than antibiotics
 ANTIMICROBIAL DRUGS cont’d

Bactericidal: killing bacteria directly

Bacteriostatic: preventing bacterial

growth

Selective (differential) toxicity: a drug

kills harmful microbes without
damaging the host
 MODES OF ACTION OF
ANTIMICROBIAL DRUGS

Inhibition of cell wall synthesis: prevent

synthesis of peptidoglycan: Penicillins,
cephalosporins, bacitracin, vancomycin,
isoniazid (INH), ethambutol

Inhibition of protein synthesis: interfere with

70S ribosome function: Aminoglycosides,
tetracyclines, chloramphenicol, macrolides
 MODES OF ACTION OF ANTIMICROBIAL DRUGS cont’d

Inhibition of nucleic acid synthesis: interfere

with transcription & replication: Rifamycins
(rifampin), quinolones, fluoroquinolones
(including ciprofloxacin)
Injury to the plasma membrane: disruption &
change in permeability: Polymyxin B
Inhibition of essential metabolite synthesis:
competitive inhibition of enzyme activity:
Sulfonamides (sulfa drugs, including
trimethoprim and sulfamethoxazole)
 Inhibition of Cell Wall Synthesis
• Penicillin: natural vs. semisynthetic

• Polypeptide antibiotics:
Bacitracin: Topical
application; against
gram-positives

Vancomycin: Glycopeptide; Important

"last line" against antibiotic resistant
S. aureus
 Inhibition of Cell Wall Synthesis
• Cephalosporins: 2nd, 3rd, and 4th
generations more effective against gram-
negatives
• Antimycobacterial (tuberculosis)
antibiotics:
Isoniazid (INH): Inhibits mycolic acid
synthesis
Ethambutol: Inhibits incorporation of
mycolic acid
Bacterial growth inhibited by penicillin
Photo Taken by Alexander Fleming in 1928
 Penicillin prevents synthesis of
peptidoglycan in bacterial cell walls; blocks
cross-linking of peptide chains

Penicillin is bacteriostatic; prevents growth but

doesn’t kill bacteria until they try to multiply
Inhibition of bacterial
cell wall synthesis by
penicillin
Retention of Penicillin G
Inhibition of Protein Synthesis (mRNA translation)
Inhibition of Protein Synthesis (mRNA translation)

• Chloramphenicol: Broad spectrum

Binds to 50S ribosome subunit,
inhibits peptide bond formation

• Aminoglycosides: Streptomycin,
neomycin, gentamycin
Broad spectrum, change shape of
30S subunit
Inhibition of Protein Synthesis (mRNA translation)

• Tetracyclines: Broad
spectrum, interfere with
tRNA attachment

• Macrolides: Gram-
positives; bind to 50S,
prevent translocation;
Example - erythromycin
 Inhibition of Nucleic Acid Synthesis
• Rifamycin (Rifampin): Inhibits RNA
synthesis, antimycobacterial (tuberculosis)
• Quinolones & fluoroquinolones:
Ciprofloxacin; Inhibits DNA gyrase

Injury to the Plasma Membrane

• Polymyxin B: Topical;
combined with bacitracin
& neomycin in over-the-
counter preparation
Competitive Inhibition of Synthesis of Essential Metabolites

Sulfonamides (Sulfa drugs):

• Inhibit folic acid synthesis from PABA
• Broad spectrum

(Sulfa drug)
(PABA)

PABA not converted to folic acid Bacterial cell dies

Competitive inhibition

Competitive inhibition

Synergy between
Sulfamethoxazole
& Trimethoprim
TESTS FOR ANTIBIOTIC SUSCEPTIBILITY

 Disk Diffusion (Kirby-Bauer) test: zone

of inhibition forms around paper disk
containing antibiotic; size of zone
correlates with level of susceptibility
 
Minimal Inhibitory Concentration (MIC):
lowest antibiotic concentration that
prevents visible bacterial growth;
determined by E test or serial dilution
 Disk Diffusion (Kirby-Bauer) Test

Antibiotic
disks
planted
onto a
medium
streaked
with test
organism
 After
incubation,
zones of
inhibition are
measured
 MIC -Serial Dilution

400 300 200 100 50 ug/mL

MIC E Test
E Test & Disk
Diffusion
 ANTIBIOTIC RESISTANCE
Bacteria in culture or an infection can become
resistant to antibiotics through mutation or
genetic recombination

Resistant strains can spread globally, threatening

our ability to treat diseases

Important examples include:

• Methicillin-resistant Staphylococcus aureus (MRSA)
• Vancomycin-resistant Enterococcus (VRE)
• Carbapenem-resistant Enterobacteriaceae (CRE)
• Multiply drug-resistant Mycobacterium tuberculosis
 ANTIBIOTIC RESISTANCE
Develops by 4 general mechanisms:
• Destruction or inactivation of the drug (e.g., beta-
lactamase)
• Preventing penetration to the target site within
the microbe (e.g., tetracycline resistance)
• Alteration of the drug’s target sites (e.g., a single
amino acid change in ribosomal protein)
• Rapid ejection (efflux) of the drug out of the cell
Resistance can arise through mutation and is often
transmitted between microbes by plasmids
4 Main Mechanisms of Antibiotic Resistance
Penicillinase: Some bacteria produce
penicillinase (-lactamase) enzyme that
cleaves the -lactam ring of penicillin

Produced by bacterium

Not Antimicrobial
Cephalosporins
are resistant to
penicillinase
because they
have a different
nucleus
Development of Antibiotic Resistance During Antibiotic Therapy
Nonprescription
antibiotics resistance
 ANTIVIRAL DRUGS
Nucleoside & Nucleotide Analogs block viral nucleic acid
synthesis by formation of false nucleotides
(Examples: Acyclovir, Ganciclovir, Zidovudine)
Other Enzyme Inhibitors block virus-specific enzymes such
as neuraminidase [Example: Oseltamivir (Tamiflu)]
Antiretroviral Drugs for HIV
Protease Inhibitors inhibit enzymes that control the
maturation of viral particles (blocks cutting up of large
proteins into fragments by proteases)
(Examples: Indinavir and saquinavir for HIV)
Integrase Inhibitors inhibit enzyme that integrates viral DNA
(provirus) into host cell DNA (Example: Raltegravir)
Entry Inhibitors target HIV recptors used for binding to cell
(Example: Maraviroc)
Fusion Inhibitors blocks fusion & entry into cell (Example:
Enfuvirtide)
 ANTIVIRAL DRUGS
Nucleoside & nucleotide analogs cause production of “false
nucleotides” in DNA
Examples: Acyclovir, ganciclovir, zidovudine (AZT)
 ANTIVIRAL DRUGS
Nucleoside & Nucleotide Analogs cont’d
 ANTIVIRAL DRUGS
Nucleoside & Nucleotide Analogs cont’d