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8/8/2019 Chapter24 Outline
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Chapter 24
Antimicrobial Drugs
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24.1 The History and Properties of
Antimicrobial Agents
The history of chemotherapy originated with Paul
Ehrlich.
Ehrlich originated the concept of selective toxicity.
Ehrlich and Sahachiro Hata discovered the
effectiveness of arsphenamine (Salvarsan)
against the syphilis spirochete.
Prontosil was a red dye found to inhibit some
gram-positive bacterial species.
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Alexander Fleming¶s serendipitous discovery of
penicillin ushered in the era of antibiotics. Penicillium mold produces a substance that kills
gram-positive bacteria.
FIGURE 02a: Alexander Fleming and his
culture of Penicillium
FIGURE 24.2b: Photograph of Fleming¶s
culture plate
© Science Source, photo by Dean Pausett/PhotoResearchers, Inc.
© National Library of Medicine
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Antimicrobial agents have a number of importantproperties.
Synthetic agents are made in a pharmaceutical
lab.
Antibiotics are products of or derived from living
microorganisms.
Semisynthetic drugs include synthetic and
antibiotic elements.
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Selective toxicity means that a drug should harm thepathogen but not the host.
The toxic dose of a drug is the concentration causingharm to the host.
The therapeutic dose is the concentration eliminatingpathogens in the host.
Together, the toxic and therapeutic doses are used toformulate the chemotherapeutic index.
FIGURE 03: A representation of the chemotherapeutic index
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Drugs have a range of pathogens on which they will
work (antimicrobial spectrum). Broad-spectrum drugs affect many taxonomic groups.
Narrow-spectrum drugs affect only a few pathogens.
FIGURE 04: The antimicrobial spectrum of activity
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24.2 The Synthetic Antibacterial Agents
Sulfanilamide and other sulfonamides targetspecific metabolicreactions.
Sulfonamides outcompete essential folicacid components for binding sites in abacterial enzyme.
They prevent nucleicacid synthesis and DNAreplication.
FIGURE 05: The disruption of folic acid
synthesis by competitive inhibition
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Other synthetic antimicrobials have additional
bacterial cell targets.
Isoniazid interferes with cell wall synthesis in
species of My cobacterium.
Quinolones block DNA synthesis in bacteria.
FIGURE MM05: IsoniazidFIGURE MM06: Ciproflozacin
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24.3 The Beta-Lactam Family of Antibiotics
Penicillin has remained the most widely usedantibiotic.
Penicillins are active against many gram-positiveand some gram-negative bacteria.
They interfere with cell wall synthesis, causing thecell to burst.
FIGURE 06: Some
members of the penicillin
group of antibiotics
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Some individuals experience an anaphylactic allergic
reaction. Many penicillin-resistant species produce beta-
lactamases that inactivate penicillin.
Numerous semisynthetic penicillins have been
developed.
FIGURE 07: The action of penicillinase on sodium penicillin G
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Other beta-lactam antibiotics also inhibit cell wall synthesis.
Cephalosporins are broader spectrum alternatives to
penicillins.
Monobactams are active against aerobic, gram-negative
rods.
Carbapenems are broad spectum drugs.
For example, Imipenem
FIGURE MM08: ImipenemFigure MM07: Cephalosporin
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24.4 Other Bacterially Produced
Antibiotics Vancomycin also
inhibits cell wall
synthesis.
It is effective against
gram-positive
bacteria such as
staphylococci.
Side effects include
damage to the ears
and kidneys.FIGURE 10: The targets for antibacterial agents
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Bacitracin interferes with
transport of cell wall precursors
through the membrane.
It is toxic internally, so is usedtopically.
Polymyxins increase
membrane permeability of gram-negative rods.
Polypeptide antibiotics affect the cell membrane.
FIGURE MM10: Bacitracin
FIGURE MM09: Vancomycin
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Many antibiotics affect protein
pynthesis. Aminoglycosides attach to
bacterial ribosomes, blockingtranscription.
Streptomycin is sometimesused in tuberculosis cases.
Gentamicin is used againstgram-negative infections inthe urinary tract.
Neomycin is used as anointment in combination withpolymyxin and bacitracin asNeosporin.
FIGURE MM11
: Streptomycin
FIGURE MM12: Gentamicin
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Chloramphenicol is used against a wide variety of
bacteria and some rickettsiae and fungi.
It is reserved for serious infections like:
± meningitis;
± cholera;
± typhoid and typhus fevers;
± Rocky Mountain spotted fever .
Severe side effects include aplastic anemia and gray
syndrome in newborns.
Figure 08: Antibiotics and
Their Affect on
Protein Synthesis.
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Tetracyclines are broad spectrum antibiotics that
target the attachment of tRNA to the 30S subunit.
They have a benzene ring formation.
They can destroy intestinal microbiota and cause staining
of the teeth.
FIGURE 09a: The structure of doxycyclineFIGURE 09b: The staining of teeth
associated with tetracycline use© Kenneth E. Greer/Visuals Unlimited
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The macrolide erythromycin is used againstgram-positive bacteria.
Clindamycin is a semisynthetic drug used
against penicillin-resistant bacteria.
Pseudomembranous colitis can occur .
Streptogramins are effective against gram-positive bacteria.
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Oxazolidinones (like Zyvox) are effectiveagainst gram-positive bacteria, including
multidrug-resistant S taphy lococcus aureus,
killed, allowing Clostridium difficile to flourish.
Some antibiotics inhibit nucleic acid synthesis.
Rifampin interferes with RNA synthesis.
It is effective against tuberculosis, leprosy,
and meningitis.
It can cause liver damage.
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24.5 Antifungal and Antiparasitic Agents
Several Classes of Antifungal Drugs Cause MembraneDamage
Polyenes bind to ergosterol in fungal plasma membranes,causing contents to leak out.
Nystatin is used against Candida albicans infections. Amphotericin B is used against serious systemic fungal
infections.
Imidiazoles inhibit an enzyme needed to form ergosterol inthe fungal plasma membrane.
They are used for cutaneous and systemic infections.
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Echinocandins inhibit fungal cell wall synthesis.
Caspofungin is used to treat invasivecandidiasis and aspergillosis.
Flucytosine interrupts nucleic acid synthesis.
It is active against strains of Candida and
Cr y ptococcus.
Griseofulvin binds to microtubules, inhibitingmitosis.
It is used against ringworm and athlete¶s foot.
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The goal of antiprotozoal agents is to eradicate the
parasite.
Aminoquinolines are antimalarial drugs that accumulate
in parasitized red blood cells.
They interfere with the parasite¶s ability to break down
and digest hemoglobin.
Sulfonamides block folic acid synthesis as they do for
bacteria.
Nitroimidazoles interfere with DNA synthesis.
They are used to treat amebiasis, giardiasis and
trichomoniasis.
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A derivative of arsenic is used against African
trypanosomiasis.
A derivative of antimony is used against leishmaniasis (as is
pentamidine).
Artemisinin destroys malarial
parasites by releasing free
radicals in red blood cells.
FIGURE
MM25:
Artemisnin
FIGURE 12: The source of artemisinin
© Jack Barker/Alamy Images
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Antihelminthic agents are targeted at nondividinghelminths.
Praziqyantel changes membrane permeability incestodes and trematodes.
This causes contraction and paralysis in the parasite.
Mebendazole: inhibits nutrient uptake in worms
in the host intestine.
disrupts microtubules and cell
division.
Avermectins cause paralysis
in a number of roundworms.
FIGURE MM26: Praziquantel
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24.6 Antibiotic Assays and Resistance
There are several
antibiotic susceptibility
assays.
The tube dilutionmethod determines
the minimum
inhibitory
concentration.
FIGURE 13ab: Determination of minimal
inhibitory concentration
Source: Data modified from the InternationalJournal of Applied Research in VeterinaryMedicine.
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The agar disk diffusion method involves different antibiotics
diffusing from paper disks in a bacterial colony.
FIGURE 14: Antimicrobial susceptibility testing
Courtesy of Dr . Richard Facklam/CDC
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There are four mechanisms of antibiotic resistance.
Many species of bacteria have evolvedresistance to certain antibiotics and syntheticagents.
The evolution of strains of S . aureus resistantto multiple drugs is particularly alarming.
1. Resistance to sulfonamides may develop if thebacterial enzyme changes or if the bacteria
evolves an alternate metabolic pathway.
2. Bacteria may evolve the ability to enzymaticallyinactivate an antibiotic.
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3. Bacteria may evolve the ability to prevent drug
entry into the cytoplasm or to pump the drug outof the cytoplasm.
4. Bacteria can evolve changes in drug targets like
ribosomes or enzymes involved in replication.
Figure 16: Types of
Antibiotic Resistance.
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Antibiotic resistance is of
grave concern in themedical community.
Improper or excessive
use of antibiotics
causes antibioticresistance.
If resistant strains spread
to other patients, asuperinfection occurs.
Figure 17: The Possible Outcomes of Antibiotic Treatment.
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Antibiotics are available over the counter in
developing countries, allowing for overuseand incorrect use.
Antibiotic use is widespread in livestock
feeds.
They can be transmitted to humansthrough meat consumption.
Figure 19: Annual Global
Production of Antibiotics.