chapter24 outline

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Chapter 24

Antimicrobial Drugs



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.



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



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.



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



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



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



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



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



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



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



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



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



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



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.



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



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.



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.



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.



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.



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.



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



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



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.



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



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.



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.



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.



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.

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