Learning Objectives

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Learning Objectives

• Identify five modes of action of antimicrobial
  drugs
• Explain why the antibiotics are specific for
  bacteria
• List the advantages of each of the following
• Semisynthetic penicillin, Cephalosporins,
  Vancomycin
• Describe how each of the following inhibits
  protein synthesis
• Aminoglycosides, Tetracyclines,
  Chloramphenicol, Macrolides
• Compare the mode of action of polymyxin B,
  bacitracin
• Describe how rifamycins and quinolones kill
  bacteria
• Describe how sulfa drugs inhibit microbial growth

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The era of chemotherapy

• 1910
• Paul Ehrlich
• The German chemist
• Discovered Salvarsan
• Effective against Treponema pallidum

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The era of chemotherapy
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The Spectrum of Antimicrobial Activity

• Narrow spectrum (limited spectrum)
• Antimicrobials effective against a (limited
  spectrum)
• of microbial types
• A drug effective on G or G- bacteria
• Broad spectrum (extended spectrum)
• Antimicrobials effective against a (extended
  spectrum) wide
• variety of microbial types
• A drug effective against both G G- bacteria

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The Action of Antimicrobial Drugs
Bactericidal Kill microbes directly
Bacteriostatic Prevent microbes from growing
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Mechanisms of Antibiotics Action
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Mechanisms of Antibiotics Action

• 1- Inhibition of Cell Wall Synthesis
• 2- Injuring the Plasma Membrane
• 3- Inhibition of Protein Synthesis
• 4- Inhibition of Nucleic Acid Synthesis
• 5- Inhibiting the Synthesis of Essential
  Metabolites

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Inhibition of Cell Wall Synthesis
ß-Lactam antibiotics generally are bactericidal
agents
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Inhibition of Cell Wall Synthesis

• 1- Beta-Lactam Antibiotics
• Penicillins
• Cephalosporins
• 2- Glycopeptides
• Vancomycin
• 3- Lipopeptides
• Daptomycin
• 4- Polypeptides
• Bacitracin

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Beta-Lactam Antibiotics

• Penicillins
• 6-aminopenicillanic acid
• Penicillium chrysogenum

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Natural Penicillins

• Penicillin G
• Is incompletely absorbed
• Inactivated by gastric acid
• An intravenous drug
• Penicillin V
• Resistant to acid
• Oral form
• Active against
• All ß-hemolytic most other streptococci
• Meningococci most G anaerobes

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Penicillinase resistant penicillins
Nafcillin, Oxacillin, Methicillin, Cloxacillin,
Dicloxacillin Similar to natural
penicillins Enhanced activity against
staphylococci
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Broad-spectrum penicillins
1- Aminopenicillins Ampicillin,
Amoxicillin Ampicillin was limited primarily to
Escherichia Proteus species 2-
Carboxypenicillins Carbenicillin,
Ticarcillin Are effective against a broader range
of G- bacteria Klebsiella, Enterobacter,
Pseudomonas species
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Broad-spectrum penicillins
3- Ureidopenicillins Azlocillin, Piperacillin,
Mezlocillin
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Analogues

• Clavulanic acid, Sulbactam, Tazobactam
• ß- lactamase inhibitors
• Irreversibly inactivate susceptible bacterial ß-
  lactamases
• Are relatively inactive by themselves
• When combined with some penicillins are
  effective
• (ampicillin, amoxicillin, ticarcillin,
  piperacillin)
• Amoxicillin/clavulanic acid (Co-amoxiclav)
• Ampicillin/sulbactam (Sultamicillin)

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Cephalosporins

• 7-aminocephalosporanic acid
• Originally isolated from the mold Cephalosporium
• Cephamycins
• Contain O in place of S
• More stable to ß-lactamase hydrolysis

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First-generation (narrow-spectrum)
Cefazolin, Cephalexin, Cephalothin, Cephapirin,
Cephradine Escherichia coli Klebsiella
species Proteus mirabilis Oxacillin-susceptible
gram-positive cocci
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Second-generation (expanded-spectrum)
Cefamandole, Cefaclor, Cefuroxime, Cefotetan,
Cefoxitin Haemophilus influenzae Enterobacter
species Citrobacter species Serratia species Some
anaerobes, such as Bacteroides fragilis
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Third-generation (broad-spectrum)
Cefixime, Cefoperazone, Cefotaxime, Ceftazidime,
Ceftizoxime, Ceftriaxone Most Enterobacteriaceae
Pseudomonas aeruginosa
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Fourth-generation
Cefepime, Cefpirome Activity oxacillin against
gram-positive bacteria Improved gram negative
activity
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Fifth-generation
Ceftobiprole, Ceftaroline
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Carbapenems

• Imipenem, Meropenem, Ertapenem
• Broad-spectrum antibiotics
• Active against virtually all organisms
• Resistance has been reported
• All oxacillin-resistant staphylococci
• Selected Enterobacteriaceae
• Pseudomonas

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Monobactams

• Aztreonam
• Narrow-spectrum antibiotics
• Are active only against aerobic, G- bacteria
• Anaerobic bacteria and G bacteria are resistant

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Resistant to ß-lactam antibiotics

• 1) Prevention of the interaction of the
  antibiotic the target PBP
• Only in G- particularly Pseudomonas species
• Changes in the porins
• Alter the size or charge of channels
• 2) Modification of the binding of the antibiotic
  to the PBP
• I- A mutation in the PBP gene
• Penicillin resistance in Enterococcus faecium
• II- Modification of an existing PBP through
  recombination
• Penicillin resistance in Streptococcus pneumoniae
  
• III- Acquisition of a new PBP
• Escherichia coli , MRSA
• IV- An overproduction of PBP
• 3) Hydrolysis of the antibiotic by ß-lactamases

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ß-lactamases

• Serine proteases as the PBPs
• gt 200 different ß-lactamases
• Penicillinases specific for penicillins
• Cephalosporinases specific for cephalosporins
• Carbapenemases specific for carbapenems
• Four classes (A to D)

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ß-lactamases

• Class A
• The most common are SHV-l TEM-l
• Found in G- rods (e.g., Escherichia, Klebsiella)
• Minimal activity against cephalosporins
• Point mutations Extended-spectrum ß-lactamases
  ESBLs
• Are commonly encoded on plasmids

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ß-lactamases

• Class B
• Zinc dependent metalloenzymes
• Broad spectrum of activity against all ß-lactam
  antibiotics
• Class C
• Are primarily cephalosporinases
• Are encoded on the bacterial chromosome
• Class D
• Are penicillinases
• Found primarily in G- rods

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Glycopeptides Vancomycin

• Obtained from Streptomyces orientalis
• Interacts with the D-alanine-D-alanine in the
  pentapeptide
• Is inactive against G- bacteria
• Intrinsically resistant
• D-alanine-D-lactate
• Lactobacillus, Erysipelothrix
• D-alanine-D-serine
• Enterococcus gallinarum, E. casseliflavus
• Acquired resistance vanA vanB

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Polypeptides Bacitracin

• Bacillus licheniformis
• Interfering with dephosphorylation of the lipid
  carrier
• Damage cytoplasmic membrane and inhibit RNA
  transcription
• The treatment of skin infections caused by
• Staphylococcus group A Streptococcus
• Used in creams, ointments, sprays
• G- bacteria are resistant
• Resistance failure of the antibiotic to
  penetrate into the cell

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Inhibition of Cell Wall Synthesis

• Isoniazid, Ethionamide, Ethambutol, Cycloserine
• Used for the treatment of mycobacterial
  infections
• Isoniazid
• Isonicotinic acid hydrazide INH)
• Bactericidal Blocks mycolic acid synthesis
• Ethionamide
• Derivative of INH
• Blocks mycolic acid synthesis
• Ethambutol
• Interferes with the synthesis of arabinogalactan
  in the cell wall
• Cycloserine
• Inhibits D-alanine-Dalanine synthetase Alanine
  racemase

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Injuring the Plasma Membrane
1- Lipopeptides Daptomycin 2- Polypeptides Polymyx
ins
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Lipopeptides Daptomycin

• A naturally cyclic lipopeptide
• Streptomyces roseosporus
• Binds irreversibly to the CM.
• Disruption of the ionic gradients
• Active against G bacteria
• G- bacteria are resistant

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Polypeptides Polymyxins

• Cyclic polypeptides
• Bacillus polymyxa
• Interacting with LPS the phospholipids in the
  OM
• Increased cell permeability
• Polymyxin B E (Colistin) causing serious
  nephrotoxicity
• Localized infections external otitis, eye
  skin infections

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Inhibition of Protein Synthesis
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Inhibition of Protein Synthesis
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Aminoglycosides

• Amino sugars --- Glycosidic Bond--- Aminocyclitol
  ring
• Bactericidal
• Bind irreversibly to ribosomal proteins
• Misreading of the messenger RNA (mRNA)
• Premature release of the ribosome from
  mRNA
• Streptomycin, Neomycin, Kanamycin, Tobramycin
• Streptomyces species
• Gentamicin Sisomicin
• Micromonospora species
• Amikacin from kanamycin
• Netilmicin from sisomicin
• Systemic infections caused by many G- rods

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Aminoglycosides

• Resistance
• 1- Mutation of the ribosomal binding site
• 2- Decreased uptake of the antibiotic (Anaerobic
  bacteria)
• 3- Increased expulsion of the antibiotic from the
  cell
• 4- Enzymatic modification
• The most common mechanism of resistance
• Phosphotransferases (APHs 7 described)
• Adenyltransferases (ANTs 4 described)
• Acetyltransferases (AACs 4 described)

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Tetracyclines

• Broad-spectrum
• Bacteriostatic
• Tetracycline, Doxycycline, Minocycline
• Binding reversibly to the 30S
• Blocking the binding of aminoacyl-tRNA
• Chlamydia, Mycoplasma, Rickettsia

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Tetracyclines
Resistance 1- Decreased penetration of the
antibiotic 2- Active efflux of the antibiotic out
of the cell 3- Alteration of the ribosomal target
site 4- Enzymatic modification of the antibiotic
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Glycylcycline

• Tigecycline
• Semisynthetic derivative of minocycline
• Inhibits protein synthesis as the tetracyclines
• Broad spectrum of activity G, G- anaerobic
  bacteria
• Resistant Bacteria
• Proteus
• Morganella
• Providencia
• Pseudomonas aeruginosa

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Oxazolidinones

• Linezolid
• Narrow-spectrum
• Block initiation of protein synthesis
• (70S initiation complex)
• Binds to the 50S ribosomal subunit
• Mechanism of resistance
• Target site modification

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Chloramphenicol

• Broad spectrum
• Bacteriostatic
• Blocking peptide elongation
• Binding reversibly to the peptidyl transferase
  (50S)
• Only for the treatment of typhoid fever
• Can produce aplastic anemia (1 per 24,000
  treated patients)
• Resistance plasmid-encoded chloramphenicol
  acetyltransferase

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Macrolides

• Erythromycin, Azithromycin, Clarithromycin
• Streptomyces erythreus
• Broad spectrum
• Bacteriostatic
• Blocks polypeptide elongation
• Reversible binding to the 23S rRNA
• Used to treat pulmonary infections
• Mycoplasma, Legionella, Chlamydia species
• Infections caused by Campylobacter species
  

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Macrolides
Resistance 1- Alteration of the ribosomal target
site Methylation of the 23S rRNA 2-
Enzymatic modification of the antibiotic
Destruction of the lactone ring by an
erythromycin esterase 3- Mutations in the 23S
rRNA ribosomal proteins
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Ketolides

• Telithromycin
• Semisynthetic derivatives of erythromycin
• Increase stability in acid
• Blocks protein synthesis as Macrolides
• Broad-spectrum antibiotic
• Active against some macrolide
• resistant staphylococci enterococci

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Lincosamide

• Clindamycin
• Derivative of lincomycin (Streptomyces
  lincolnensi)
• Inhibits peptidyl transferase
• Block the binding of the amino acid-acyltRNA
  complex
• Resistance Methylation of the 23S ribosomal RNA

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Streptogramin

• Streptogramin
• Cyclic peptides
• Streptomyces species
• Group A and group B
• Quinupristin-dalfopristin (Synercid)
• Dalfopristin prevents peptide chain elongation
• Quinupristin initiates premature release of
  peptide

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Inhibition of Nucleic Acid Synthesis
1- Quinolones 2- Rifampin 3- Metronidazole
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Quinolones

• Synthetic
• Inhibit bacterial DNA gyrases (II) or
  topoisomerases (IV)
• Nalidixic acid
• Fluoroquinolones
• Ciprofloxacin Levofloxacin
  Gatifloxacin
• Resistance mutations in chromosomal genes of DNA
  gyrases (II)
• or topoisomerases (IV)

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Rifampin

• Semisynthetic derivative of rifamycin B
• Streptomyces mediterranei
• Inhibits the initiation of RNA synthesis
• Bactericidal
• Mycobacterium tuberculosis
• Staphylococci
• Streptococci
• Resistance a mutation in the chromosomal gene
• that codes for the ß subunit of RNA polymerase
  (In G)

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Metronidazole

• Reduction of its nitro group by bacterial
  nitroreductase
• Producing cytotoxic compounds that disrupt the
  host DNA
• Anaerobic bacterial infections (B. fragilis)
• Resistance
• 1- Decreased uptake
• 2- Elimination of the cytotoxic compounds

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Antimetabolites

• Sulfonamides
• Preventing the synthesis of the folic acid
• Compete with p-aminobenzoic acid
• Mammalian organisms do not synthesize folic acid

Treatment of Nocardia, Chlamydia, some protozoa
infections
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Antimetabolites

• Trimethoprim
• Blocks the conversion of dihydrofolate to
  tetrahydrofolate
• Inhibiting dihydrofolate reductase
• Trimethoprim sulfamethoxazole Synergistic
  combination
• Treatment of acute and chronic urinary tract
  infections
• Resistance
• Permeability barriers Pseudomonas
• Decreased affinity of dihydrofolate reductase

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Mechanisms of Resistance
1- Enzymatic Destruction or Inactivation of the
Drug 2- Prevention of Penetration to the Target
Site 3- Alteration of the Drug's Target Site 4-
Rapid Efflux (Ejection) of the Antibiotic
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Antibiotic Assays
The disk agar diffusion (DAD) method
involves Different antibiotics diffusing from
paper disks in a bacterial colony
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Antibiotic Assays
The tube dilution method determines the minimum
inhibitory concentration (MIC)
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