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Presentations prepared by
Bradley W. Christian,
McLennan Community
College
CHAPTER
20
Antimicrobial
Drugs
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 Selective toxicity: selectively finding and destroying
pathogens without damaging the host.
 Chemotherapy: the use of chemicals to treat a disease.
 Antibiotic: a substance produced by a microbe that, in
small amounts, inhibits another microbe.
 Antimicrobial drugs: synthetic substances that interfere
with the growth of microbes.
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The History of Chemotherapy
 1928: Fleming discovered penicillin, produced by
Penicillium.
 1932: Prontosil red dye used for
streptococcal infections.
 1940: Howard Florey and Ernst
Chain performed first clinical
trials of penicillin.
 Today there is a growing
problem of antibiotic resistance.
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Figure 20.1 Laboratory observation of antibiosis.
Staphylococcus aureus
Fleming and Penicillin
Penicillium notatum
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Table 20.1 Representative Sources of Antibiotics
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The Spectrum of Antimicrobial Activity
 Narrow spectrum of microbial activity: drugs that affect
a narrow range of microbial types.
 Broad-spectrum antibiotics: affect a broad range of
gram-positive or gram-negative bacteria.
 Superinfection: overgrowth of normal microbiota that is
resistant to antibiotics.
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The Spectrum of Antimicrobial Activity
分枝桿菌
Narrow spectrum
Broad spectrum
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The Action of Antimicrobial Drugs
 Bactericidal agent 殺菌劑:Kill microbes directly
 Bacteriostatic agent 抑菌劑:Prevent microbes from
growing
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 Bacteria have their own enzymes for
 Cell wall formation
 Protein synthesis
 DNA replication
 RNA synthesis
 Synthesis of essential metabolites
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Figure 20.2 Major Action Modes of Antibacterial Drugs.
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Inhibiting Cell Wall Synthesis
 Ex: Penicillin 青黴素
 Prevent the synthesis of intact peptidoglycan
 Natural penicillins
 Semisynthetic penicillins
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Figure 20.3 The inhibition of bacterial cell wall synthesis by penicillin.
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Inhibiting Protein Synthesis
氯黴素
鏈黴素
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四環黴素
Figure 20.4 The inhibition of protein synthesis by antibiotics.
Injuring the Plasma Membrane
 Ex: polypeptide antibiotics
 Cause change in the permeability of the plasma
membrane
 Ex: antifungal drugs – amphotericin
B, miconazole, ketoconazole
 Combine with sterols in the fungal
plasma membrane to disrupt the
membrane
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Figure 20.5 Injury to the plasma membrane
of a yeast cell caused by an antifungal drug.
Inhibiting Nucleic Acid Synthesis
 This kind of drugs interfere the processes of DNA
replication and transcription and have an extremely
limited usefulness.
 Ex: rifampin and quinolone
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Inhibiting the Synthesis of Essential Metabolites
 Competitively inhibition: a substance (antimetabolite)
that closely resemble the normal substrate for the
enzyme.
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Figure 5.7
 Ex: antimetabolite sulfanilamide v.s. para-aminobenzoic
磺苯醯胺 (磺胺類)
acid (PABA)
葉酸
 many microorganisms synthesize folic acid from
PABA, but human do not
selective toxicity
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Table 20.3 Antibacterial Drugs (1 of 2)
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Table 20.3 Antibacterial Drugs (2 of 2)
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Table 20.4 Differential Grouping of Cephalosporins
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Table 20.5 Antifungal, Antiviral, Antiprotozoan, and Antihelminthic Drugs (1 of 2)
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Table 20.5 Antifungal, Antiviral, Antiprotozoan, and Antihelminthic Drugs (2 of 2)
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Common Antimicrobial Drugs
Antibacterial Antibiotics: Inhibitors of Cell Wall
Synthesis
 Penicillin: contain a β-lactam ring; Types are differentiated
by the chemical side chains attached to the ring.
 Natural penicillins
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Figure 20.6a
Figure 20.7 Retention of penicillin G.
Penicillin G (injected intramuscularly)
Penicillin G (oral)
Procaine penicillin
Benzathine penicillin
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 Natural penicillins have some disadvantages:
 Narrow spectrum
 Susceptibility to penicillinases
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Figure 20.8
 Semisynthetic penicillins: Contain chemically added side
chains, making them resistant to penicillinases
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Figure 20.6b
 Penicilinase-resistant penicillins
 Methicillin → oxacillin, nafcillin were developed to against
MRSA (methicillin-resistant Staphylococcus aureus)
 Extended-spectrum penicillins: Effective against gramnegatives as well as gram-positives
 Aminopenicillin (ex: ampicillin, amoxicillin)
 Carboxypenicillin (ex: carbenicillin, ticarcillin)
 Ureidopenicillin (脲基青黴素，加上H2NCONH- ，ex:
mezlocillin, azlocillin)
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Aminopenicillin
Penicillin
Ampicillin
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Amoxicillin
Carboxypenicillin
Penicillin
Carbenicillin
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Ticarcillin
Ureidopenicillin
Penicillin
Azlocillin
Mezlocillin
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 Penicillins plus -lactamase inhibitors
 Amoxicillin + potassium clavulanate
 Carbapenems
 Substitute a C for a S and add a
double bond
 Monobactam
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 Cephalosporins 頭芽孢菌素抗生素
 Work similar to penicillins
 β-lactam ring differs from
penicillin
 Grouped according to
their generation of
development
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Figure 20.9
 Polypeptide antibiotics
 Bacitracin 枯草桿菌素
 Topical application
 Against gram-positives
 Vancomycin 萬古黴素
 Glycopeptide
 Important "last line" against
antibiotic resistant S.
aureus
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Antimycobacterial Antibiotics
 Isoniazid (INH)
 Inhibits mycolic acid synthesis in mycobacteria
 Ethambutol
 Inhibits incorporation of mycolic acid into the cell wall
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The Inhibitors of Protein Synthesis
氯黴素
鏈黴素
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四環黴素
Figure 20.4
Inhibitors of Protein Synthesis
 Chloramphenicol 氯黴素
 Synthesized chemically; broad spectrum
 Binds 50S subunit, inhibits peptide bond formation
 Can suppress bone marrow and affect blood cell
formation
Figure 20.10
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 Aminoglycosides (胺基醣苷類): amino sugar is linked by
glycoside bond
 Broad spectrum
 Changes shape of 30S subunit
 Can cause auditory damage
 Ex: streptomycin, neomycin, gentamycin, kanamycin
健大黴素
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streptomycin
neomycin
gentamycin
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kanamycin
 Tetracyclines 四環黴素
 Broad spectrum
 Interferes with tRNA carrying the
aa to the ribosome
 Glycylcyclines 甘胺酰四環素類
 New class of antibiotics since 2000,
similar to tetracyclines
 Broad spectrum, useful against MRSA
 Binds 30S subunit, blocks protein synthesis
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Figure 20.11
 Macrolides 巨環類
 Ex: erythromycin
 Narrow spectrum against
Gram-positives
 Binds 50S, blocking
the tunnel translocation
 Streptogramins 鏈陽性菌素
 Against Gram-positives (vancomycinresistance)
 Binds 50S subunit, inhibits translation
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紅黴素
Figure 20.12
 Oxazolidinones 環氧酮類
 New class of antibiotics developed in
response to vacomycin resistance
 Against Gram-positives
 Binds 50S/30S subunit interface
 Pleuromutilins 截短側耳素
 New class of antibiotics since 2000
 Binds 50S, prevents translocation
 Ex: Retapamulin - topical and effective
against gram-positives
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Injury to the Plasma Membrane
 Affects synthesis of bacterial plasma membranes
 Lipopeptides – ex:
 Ex: Daptomycin
 Produced by streptomycetes; used for skin infections
 Attacks the bacterial cell membrane
 Ex: polymyxin B
 Topical; bacteriocidal; effective against gram-negatives
 Combined with bacitracin and neomycin in
nonprescription ointments
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Nucleic Acid Synthesis Inhibitors
 This kind of drugs interfere the processes of DNA replication
and transcription and have an extremely limited usefulness.
 Rifamycin (rifampin)
 Inhibits RNA synthesis
 Penetrates tissues; antitubercular activity
 Quinolones and fluoroquinolones
 Inhibits DNA gyrase
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Competitive Inhibition of Essential Metabolites
 Sulfonamides (sulfa drugs)
 Inhibit the folic acid synthesis needed for nucleic acid
and protein synthesis
 Competitively bind to the enzyme for PABA
production, a folic acid precursor
 Combination of trimethoprim and sulfamethoxazole
(TMP-SMZ) is an example of drug synergism
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Figure 20.13 Actions of the antibacterial synthetics trimethoprim and sulfamethoxazole.
Synergism
協同作用
SMZ
TMP
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Antifungal Drugs
 Agents affecting fungal sterols: Interrupt the synthesis of
ergosterol, making the membrane excessively permeable
 Polyenes
 Amphotericin B
 Azoles
 Miconazole
 Triazoles
 Allylamines
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 Agents affecting fungal walls
 Echinocandins
 Inhibit synthesis of -glucan.
 Agents inhibiting nucleic acids
 Flucytocine
 Cytosine analog interferes with RNA synthesis.
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 Other antifungal drugs:
 Griseofulvin: Produced by Penicillium; inhibits microtubule
formation; active against superficial dermatophytes
 Tolnaftate: used for athlete's foot; action unknown.
 Pentamidine: Anti-Pneumocystis; maybe bind to DNA
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Antiviral Drugs
 Entry and fusion inhibitors
 Block the receptors on the host cell that bind to the virus
 Block fusion of the virus and cell
 Uncoating, genome integration, and nucleic acid
synthesis inhibitors
 Prevent viral uncoating
 Inhibit viral DNA integration into the host genome
 Nucleoside analogs inhibit RNA or DNA synthesis
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Figure 20.16a The structure and function of the antiviral drug acyclovir.
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Figure 20.16b-c The structure and function of the antiviral drug acyclovir.
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 Interference with assembly and release of viral particles
 Protease inhibitors: Block the cleavage of protein
precursors
 Exit inhibitors
 Inhibit neuraminidase, an enzyme required for some
viruses to bud from the host cell
 Interferons
 Produced by viral-infected cells to inhibit further spread
of the infection
 Imiquimod: Promotes interferon production
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 Antivirals for Treating HIV/AIDS
 Antiretroviral: implies that a drug is used to treat HIV
infections.
 Nucleoside analog (zidovudine)
 Nucleotide analog (tenofovir)
 Non-nucleoside inhibitors (nevirapine)
 Protease inhibitors (atazanavir)
 Integrase inhibitors (raltegravir)
 Entry inhibitors (miraviroc)
 Fusion inhibitors (enfuvirtide)
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Antiprotozoan and antihelminthic Drugs
 Antiprotozoan drugs
 Quinine (奎寧，金雞納霜), chloroquine: preventing
malaria
 Artemisinin: Kills Plasmodium that causes malaria
 Metronidazole (Flagyl): damages DNA, also against
anaerobic bacteria
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 Antihelminthic drugs
 Niclosamide: prevents ATP generation
 against tapeworms
 Praziquantel: alters membrane permeability
 against flatworms
 Mebendazole: inhibits nutrient absorption
 against intestinal roundworms
 Ivermectin: Paralyzes worm
 against intestinal roundworms
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Tests to Guide Chemotherapy
The Diffusion Methods
 Disk-diffusion method (Kirby-Bauer test):
 zone of inhibition
Figure 20.17 The disk-diffusion method for determining the
activity of antimicrobials.
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 E test
 Determines the minimal
inhibitory concentration
(MIC) 最小抑菌濃度
Figure 20.18 The E test (for epsilometer), a gradient diffusion
method that determines antibiotic sensitivity and estimates minimal
inhibitory concentration (MIC).
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Broth Dilution Tests
 The diffusion methods doesn’t determine whether a
drug is bactericidal and not just bacteriostatic.
 Broth dilution test:
 Determine the MIC and MBC (minimal bactericidal
concentration, 最小殺菌濃度)
 Test organism is placed into the wells of a tray
containing dilutions of a drug; growth is determined
 Antibiograms: Reports that record the susceptibility of
organisms encountered clinically
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Figure 20.19 A microdilution, or microtiter, plate used for testing for minimal inhibitory concentration (MIC) of
antibiotics.
Concentration of
drug on plates
Highest
Lowest
Doxycycline
(White spots show growth in all wells;
bacterium is resistant)
Sulfamethoxazole
(Trailing end point; usually read where there
is an estimated 80% reduction in growth)
Streptomycin
(No growth in any well; bacterium is sensitive at all
concentrations)
Ethambutol
(Growth in fourth wells;
bacterium is equally sensitive to
ethambutol and kanamycin)
Kanamycin
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Resistance to Antimicrobial Drugs
 Persister cells: microbes with genetic characteristics
allowing for their survival when exposed to an antibiotic
 Superbugs: bacteria that are resistant to large
numbers of antibiotics
 Resistance genes are often spread horizontally among
bacteria on plasmids or transposons via conjugation or
transduction
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Mechanisms of Resistance

A variety of mutations can lead to antibiotic resistance.

Mechanisms of antibiotic resistance
 Enzymatic destruction or inactivation of drug
 Prevention of penetration to the target site within the
microbe
 Alteration of drug's target site
 Rapid efflux (ejection) of the antibiotic
 Variations of mechanisms of resistance

Resistance genes are often on plasmids or
transposons that can be transferred between bacteria.
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Figure 20.20 Bacterial Resistance to Antibiotics.
1. Blocking entry
Antibiotic
2. Inactivation by enzymes
KEY CONCEPTS
•
Antibiotic
Antibiotic
Altered target
molecule
Enzymatic action
3. Alteration of target molecule
Inactivated
antibiotic
4. Efflux of antibiotic
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•
There are only a few mechanisms of
microbial resistance to antimicrobial
agents: blocking the drug's entry into
the cell, inactivation of the drug by
enzymes, alteration of the drug's
target site, efflux of the drug from the
cell, or alteration of the metabolic
pathways of the host.
The mechanisms of bacterial
resistance to antibiotics are limited.
Knowledge of these mechanisms is
critical for understanding the
limitations of antibiotic use.
Figure 20.21 The development of an antibiotic-resistant mutant during antibiotic therapy.
Initiation of
antibiotic therapy
Bacteria
count
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Antibiotic resistance of bacterial
population measured by amount of
antibiotic needed to control growth
Antibiotic Misuse
 Misuse of antibiotics selects for resistance mutants.
 Misuse includes:
 Using outdated or weakened antibiotics.
 Using antibiotics for the common cold and other
inappropriate conditions.
 Use of antibiotics in animal feed.
 Failure to complete the prescribed regimen.
 Using someone else's leftover prescription.
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Effects of Combinations of Drugs
 Synergism occurs when
the effect of two drugs
together is greater than
the effect of either alone.
Figure 20.23 An example of synergism between two
different antibiotics.
 Antagonism occurs when the effect of two drugs
together is less than the effect of either alone.
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Future of Chemotherapeutic Agents
 Antimicrobial peptides
 Broad spectrum antibiotics from plants and animals
 Squalamine (sharks)
 Protegrin (pigs)
 Magainin (frogs)
 Phage therapy
 Bacteriocins: antimicrobial peptides produced by
bacteria
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