25AntimicrobialDrugs K_H 421 204

7/31/2019 25AntimicrobialDrugs K_H 421 204

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ANTIMICROBIAL

DRUGS



Antimicrobial Drugs

I. Terminology

II. History

III. Spectrum of antimicrobial activity IV. Action of antimicrobial drugs

V. A survey of commonly used

antimicrobial drugsVI. Test to determine chemotherapy

VII. Effectiveness of Drugs



I. Terminology

Antimicrobial drugs are chemotherapeutic drugs.

Two categories:

– antibiotics Antimicrobial drugs produced by

microorganisms.

– synthetic drugs Antimicrobial drugs

synthesized in the lab.

» Antibacterial synthetic drugs

» Antifungal synthetic drugs

» Antiviral agents



II. History

Paul Ehrlich (1910)

– Knew: some dyes bind better to

microorganisms than to animal cells.

– He bound a poison to a dye. Gave it to rabbits

with syphilis.

– The pathogen (Treponema pallidum) was

killed: the host was not harmed. – Was a “magic bullet”



II. History, cont.

Alexander Fleming (1928)

– In England, noticed that S. aureus did not grow

around a colony of mold on agar

– The mold was Penicillium notatum.

– He isolated the inhibitory substance. Called it

penicillin.

– Penicillin was unstable.



II. History, cont.

Florey and Chain (1940)

– In England

– Resumed study of penicillin – Isolated and purified penicillin

– USA became involved

– Penicillin used during WWII



II. History, cont.

Penicillin is an antibiotic.

“Antibiotic” is from antibiosis, meaning

against life.antibiotic A substance that is produced by

one microorganism (a bacterium or fungus)

that kills or inhibits the growth of anothermicroorganism.



II. History, cont.

Major producers of antibiotics discovered

throughout the years:

– Molds»Penicillium

»Cephalosporium

– Bacteria»Streptomyces

» Bacillus



III. Spectrum of antimicrobial

activity

Principle of selective toxicity: a drug should

selectively kill or prevent growth of a

pathogen, but not of host cells.

Differences to be considered:

– 1. Between procaryotic pathogen and

eucaryotic host

– 2. Between eucaryotic pathogen and eucaryotic

host

– 3. Between eucaryotic host and viruses



III. Spectrum of antimicrobial

activity, cont.

Narrow spectrum drugs affect only Gram-

positive cells or only Gram-negative cells.

Broad spectrum drugs affect both Gram-positive and Gram-negative cells.

The normal flora is affected, too.





IV. Action of antimicrobial drugs

Have selective toxicity

They act at a specific site, unlike

disinfectants.Are bactericidal or bacteriostatic

Or, are fungicidal or fungistatic



IV. Action of antimicrobial drugs, cont.

A. Inhibition of cell wall synthesis

B. Inhibition of protein synthesis

C. Injury to plasma membrane

D. Inhibition of nucleic acid synthesis

E. Inhibition of synthesis of essential

metabolites (F. Antifungal drugs)

(G. Antiviral drugs)





– Penicillins and cephalosporins stops synthesis

of wall by preventing cross linking of

peptidoglycan units.

– Bacitracin and vancomycin also interfere here.

– Excellent selective toxicity





– Due to differences in ribosomes

– Eucaryotic cells have 80S (60S + 40S subunits)

ribosomes.

– Procaryotic cells have 70S (50S + 30S

subunits) ribosomes.

– Examples:» Chloramphenicol and erythromycin bind to

the 50S subunit.

» Tetracyclines bind to the 30S subunit.





– Bind to membrane, alter permeability, and

cause leakage

– Or, antifungal antibiotics bind to sterols in

membrane and disrupt membrane.

» Animal cell membranes have cholesterol.

» Fungal membranes have ergosterol.» Procaryotic cell membranes have no sterols.

– Example: amphotericin B





– Stop DNA replication

» Many antiviral drugs do this.

» Example: AZT

– Or stop RNA synthesis

» Example: rifampin




E. Inhibition of synthesis of essential metabolites

– A drug mimics a normal metabolite and acts as

a competitive inhibitor.

– Enzyme of cell recognizes the drug instead of

the normal metabolite

– Pathway stops.

– Example: sulfa drugs are similar to PABA,para aminobenzoic acid.






C. Injury to plasma membraneD. Inhibition of nucleic acid synthesis


metabolites



Fig. 13-2




antimicrobial drugs

A. Inhibitors of cell wall synthesis

– 1. The penicillins

»Over 50 penicillins»Are bactericidal

»Some are naturally produced.

»Some are produced semisynthetically.»Each has a unique side chain.

»Inhibit transpeptidase activity, and

peptide crosslinking in wall





Penicillins

Common nucleus

B-lactam ring

C

N C

C

S CH3

CH3

COOHHC

CH H

O

NHC

O

R




antimicrobial drugs, cont.

– 1. The penicillins, cont.

»Side chain (R group) affects:

spectrum of penicillinpH stability

sensitivity to penicillinase, a beta-

lactamase



Penicillins

C

N C

C

S CH3

CH3

COOHHC

CH H

O

NHC

O

R

penicillinaseor

low pH

C

N C

C

S CH3

CH3

COOHH

CH H

O

NHC

O

R

H

C

OH

Penicilloic acid



Penicillins

Penicillin G

Penicillin V

CH2 C

N C

C

S CH3

CH3

COOHHC

CH H

O

NHC

O

Common nucleusO CH2

CH

NH2

Common nucleusAmpicillin






» Natural penicillins are secreted by the mold

Penicillium.

Prototype is penicillin G

Effective against Gram-positive cells,

e.g., staph and strep

Is pH sensitive. Therefore not givenorally.

Penicillin V is acid stable.

Both are susceptible to penicillinase






» Semisynthetic penicillins

Produce by growing Penicillium in

culture so that only the nucleus is

synthesized. Attach R group in lab.

Or, grow Penicillium, extract natural

penicillin, remove R group, and attachwanted R group.

Have broader spectrum. Are effective

against Gram-negative cells, too.

Are not resistant to penicillinases





A. Inhibitors of cell wall synthesis

– 1. Penicillins

– 2. Monobactams

– 3. Cephalosporins

» More than 70 available

» Similar in structure to the penicillins

» Are resistant to penicillinases

» Have broader spectrum than penicillins

» Not pH sensitive

P i illi d C h l i



Penicillins and Cephalosporins

C

N C

C

S CH3

CH3

COOHHC

CH H

O

NHC

O

R

C

N

C

C

C

S

H2

CH2 O C

CH3

O

C

CH

O

NHC

O

R

Penicillin nucleus

Cephalosporin nucleus

B-lactam ring





A. Inhibitors of cell wall synthesis, cont. – 4. Carbapenems, a new group

» Very broad spectrum

» Have a beta-lactam ring – 5. Bacitracin

» Is used topically

» Effective mainly against Gram + cells – 6. Vancomycin

» Used to treat penicillinase-producing

staphylococc.

» Ver narrow s ectrum





A. Inhibitors of cell wall synthesis, cont. – 7. Isoniazid

» Is not an antibiotic, but a synthetic drug

» Effective against Mycobacteriumtuberculosis. Stops synthesis of mycolic

acids.

» Bacteriostatic

– 8. Ethambutol

» Effective against M. tuberculosis

» Stops synthesis of mycolic acid

» Bacteriostatic



V A f l d





B. Inhibitors of protein synthesis.

– 1. Aminoglycosides

» Bactericidal

» Stop protein synthesis

» Example: Streptomycin

Used for tuberculosis

Side effect: damages 8th cranial nerve

» Other examples: neomycin & gentamicin

V A f l d





B. Inhibitors of protein synthesis, cont.

– 2. Tetracyclines

» Bacteriostatic

» Very broad spectrum

» Produced by Streptomyces

» Used in urinary tract infections

» Causes tooth discoloration, liver & kidney

damage



Tetracycline

OH

H3C OH

O

N

OH

CO OH

OH

CH3

H3C

ONH2

V A f l d






– 3. Chloramphenicol

» Bacteriostatic

» Broad spectrum

» Stops protein synthesis by binding to 50S

subunit. Stops elongation.

» Side effect is aplastic anemia.» Used for some meningitis cases and typhoid

fever

V A f l d






– 4. Macrolides

» Bacteriostatic

» Have macrocyclic lactone ring» Example: erythromycin

» Inhibits protein synthesis by binding to the

50S subunit» Narrow spectrum. Affects mainly Gram-

positive cells but some Gram- negative cells,

too.

V A f l d







C. Injury to plasma membraneD. Inhibition of nucleic acid synthesis




V A f l d






– Polymyxin B

» Bactericidal

» Effective against Gram-negative bacteria.

V A f l d






– 1. Rifamycins

» Example: Rifampin

Bactericidal

Stops transcription

Used to treat tuberculosis and leprosy

– 2. Quinolones and fluoroquinolones

» Bactericidal

V A f l d





E. Inhibition of synthesis of essential metabolites

– Sulfonamides. Also called the sulfa drugs. Are

bacteriostatic.

» Discovered by Domagk in the 1930s

He gave animals with a streptococcus

infection the dye prontosil.

The animal was cured.Put prontosil in test tube with

streptococcus, cells were not killed



V A f l d





– Sulfonamides, cont.

» Prontosil breaks down to form

sulfanilamide.

» Sulfanilamide is similar in shape to PABA.

» PABA is part of folic acid.

» Sulfanilamide is a competitive inhibitor of

enzyme that incorporates PABA into folicacid.

» Result: folic acid synthesis stops



NH2

H2

N NH

2 +

SO2NH2

NH2

NH2

H2N N N

SO2NH2

Prontosil Sulfanilamide



Sulfanilamide Para-aminobenzoic acid(PABA)

SO2NH2

NH2NH2

COOH



Folic Acid

N

NH

2N

OH

N

NCH2 N C

O

N

H

C

COOH

C

C

COOH

H2

H2

H

PABA

H

V A survey of commonly used





– Sulfonamides, cont.

» Sulfanilamide is an antimetabolite.

» Is a synthetic drug

» Humans are not affected because we get

folic acid from our diets.

» Excellent selective toxicity

» Many “sulfa” drugs are available.



III. Action of Antimicrobial Drugs













F. Antifungal drugs

– 1. Polyenes

» Amphotericin B and nystatin

» Secreted by Streptomyces

» Are fungicide

» Combines with sterols in membranes

» Used topically due to its toxicity






F. Antifungal drugs, cont.

– 2. Imidazoles and triazoles

» Interfere with sterol synthesis in fungi

» Used topically or orally

– 3. Griseofulvin

» Produced by Penicillium

» Taken orally. Accumulates in keratin, and is

found in nails, hair, skin.

» Interferes with mitosis






G. Antiviral drugs

– Antibiotics do not act on viruses.

– Difficult to get good selective toxicity against

viruses

– Relatively few approved for use in USA

– Three major groups

» 1. Amantadine» 2. Thiosemicarbazones

» 3. Base analogs






G. Antiviral drugs, cont.

– 1. Amantadine

» Acts against the influenza virus

» Prevents the virus from entering the cell or

from uncoating from capsid once inside the

cell

» Given to elderly






G. Antiviral drugs, cont.

– 2. Thiosemicarbazones

» Example: Methisazone

» Used for small pox

» Stops translation of viral mRNA

– 3. Base analogs or nucleoside analogs

» a. Idoxuridine is an analog of thymidine.

Used in eye for HSV1 infection



N

CN

C

C

CH3

O

HOCH

2O

OH

Thymidine Idoxuridine

O O

O

HOCH2O

OH

C

N

NC

I






– 3. Base analogs, cont.

»b. Acyclovir, an analog of guanine

Used to treat Herpes virusinfections

Only viral enzyme acts on acyclovir

Stops viral DNA synthesisIs only effective in cells infected

with a Herpes virus







» c. AZT, azidothymidine

An analog of thymidine

Used to treat AIDS patients

Stops RNA dependent DNA polymerase

of HIV



N

CN

C

CCH3

O

HOCH2

O

OH

Thymidine

O O

O

HOCH2O

N

C

N

NC

CH3

3

2'

4'

3'

5'

''

5'

4'

3' 2'

1' 1'

Azidothymidine(AZT)







» Also used to treat AIDS patients

ddI, dideoxyinosine

ddC, dideoxycytosine

» Others

– 4. Enzyme inhibitors

» Protease inhibitors to stop HIV replication

» Inhibitors of reverse transcriptase



Antimicrobial Drugs

I. Terminology

II. History

III. Spectrum of antimicrobial activity IV. Action of antimicrobial drugs


antimicrobial drugsVI. Test to determine chemotherapy

VII. Effectiveness of Drugs



VI. Test to determine chemotherapy

Disk diffusion method: The Kirby Bauer

Technique

– Isolate pathogen in pure culture

– Spread onto agar

– Put discs containing antibiotic on agar

– Incubate plates

– Look for zones of inhibition





Fig. 13-9



VII. Effectiveness of drugs

Bacteria may become resistant to drugs.

Occurs via:

– 1) Mutation – 2) Acquiring a plasmid, an R factor, that

contains genes coding for enzymes that

make the cell resistant to a specific

antibiotic



VII. Effectiveness of drugs, cont.

Bacterial resistance to drugs occurs by:

– 1. Inactivation of drug

»Cell secretes an enzyme thathydrolyzes antibiotic

– 2. Preventing drug entry into cell

– 3. Alteration of drug target inside cell



VII. Effectiveness of drugs, cont.

Significance of drug resistance:

– May be some cells in a population that

are resistant.

– In absence of drugs, these cells are low in

number.

– In presence of drugs, sensitive cells die,

resistant cells replicate.

– Get huge populations of resistant cells.





Fig. 13-8



Summary

Antimicrobial drugs include the antibiotics

and the synthetic drugs.

Antimicrobial drugs exhibit some selective

toxicity.

Therefore, these drugs act more specifically

than do disinfectants and antiseptics.

Documents

25AntimicrobialDrugs K_H 421 204