Antimicrobialsrms.rsccd.edu/faculty/KathyTakahashi/Bio229/ExamII...•no reliance on health care provider •patients do not always follow prescribing information •Intramuscular

Copyright © 2004 Pearson Education, Inc. publishing as Benjamin Cummings

PowerPoint® Lecture Slides for

ROBERT W. BAUMAN

MICROBIOLOGY

Chapter 10

Antimicrobials


Antimicrobial Drugs

• Chemotherapy - The use of drugs to treat a disease

• Antimicrobial drugs - Interfere with the growth of microbes within a host

• Antibiotic - Substance produced by a microbe that, in small amounts, inhibits another microbe

• Selective toxicity - A drug that kills harmful microbes without damaging the host

Copyright © 2004 Pearson Education, Inc. publishing as Benjamin Cummings Table 20.1


The Action of Antimicrobial Drugs

• Broad-spectrum

• Narrow-spectrum

• Superinfection

• Bactericidal

• Bacteriostatic


• Paul Ehrlich - 1904

• “Magic Bullets”

• Arsenic compounds for syphilis patients

• killed trypanosomes and another that worked against treponemes

• 600 derivative compounds tried

The History of Antimicrobial Agents


• Alexander Fleming

• 1928 - discovered penicillin, produced by Penicillium.

• Zone of inhibition

• 1940 – Howard Florey and Ernst Chain performed first clinical trials of penicillin.

Figure 20.1



• Gerhard Domagk -1939

• Nobel Prize for Sulfa Drugs - Sulfanilamide

• Red dye – Prontosil converts to sulfanilamide

• First antimicrobial agent used to treat wide array of infections

• Semisynthetics and synthetics


http://en.wikipedia.org/wiki/Sulfanilamide


1. Inhibition of cell wall synthesis

2. Inhibition of protein synthesis

3. Disruption of cell membrane

4. Inhibition of a metabolic pathway

5. Inhibition of DNA or RNA synthesis

6. Inhibition of pathogen attachment

Mechanisms of Antimicrobial Action



Figure 20.2

Copyright © 2004 Pearson Education, Inc. publishing as Benjamin Cummings Figure 10.3a

1. Inhibition of Cell Wall Synthesis


• Penicillin

• Natural penicillins

• Semisynthetic penicillins

Inhibitors of Cell Wall Synthesis


• Most common agents act by preventing cross-linkage of NAM subunits

• Most prominent in this group – beta-lactams;

• functional groups are beta-lactam rings

• Beta-lactams bind to enzymes that cross-link NAM subunits

• Bacteria have weakened cell walls and eventually lyse

Inhibition of Cell Wall Synthesis


Penicillins

Figure 20.6



Figure 20.8

Penicillin resistant bacteria produce the enzyme Penicillinase



Figure 10.3b

Copyright © 2004 Pearson Education, Inc. publishing as Benjamin Cummings Figure 10.3d


•Simplest beta-lactams – effective only against aerobic Gram-positive organisms

Copyright © 2004 Pearson Education, Inc. publishing as Benjamin Cummings Figure 10.3e



• Semisynthetic derivatives of beta-lactams

• More stable in acidic environments

• More readily absorbed

• Less susceptible to deactivation

• More active against more types of bacteria


Copyright © 2004 Pearson Education, Inc. publishing as Benjamin Cummings Figure 10.3c



• Cephalosporins

• 2nd, 3rd, and 4th generations more effective against gram-negatives


Figure 20.9


• Vancomycin and cycloserine

• interfere with bridges that link NAM subunits in many Gram-positives

• Bacitracin

• blocks secretion of NAG and NAM from cytoplasm

• Isoniazid and ethambutol

• disrupt formation of mycolic acid in mycobacterial species



• Prevent bacteria from increasing amount of peptidoglycan

• Have no effect on existing peptidoglycan layer

• Effective only for growing cells

• No effect on plant or animal cells; no peptidoglycan



• Prokaryotic ribosomes are 70S (30S and 50S)

• Eukaryotic ribosomes are 80S (40S and 60S)

• Drugs can selectively target translation

• Mitochondria of animals and humans contain 70S ribosomes; can be harmful

2. Inhibition of Protein Synthesis



Figure 20.4


• Chloramphenicol

• Broad spectrum

• Binds 50S subunit, inhibits peptide bond formation

• Aminoglycosides

• Streptomycin, neomycin, gentamycin

• Broad spectrum

• Changes shape of 30S subunit

Inhibitors of Protein Synthesis


• Tetracyclines

• Broad spectrum

• Interferes with tRNA attachment

• Macrolides & Erythromycin

• Gram-positives

• Binds 50S, prevents translocation

Inhibitors of Protein Synthesis

Copyright © 2004 Pearson Education, Inc. publishing as Benjamin Cummings Figure 10.4

Inhibition of Protein Synthesis

erythromycin

streptomycin


• Some drugs become incorporated into cytoplasmic membrane and damage its integrity

• Polymyxin

• disrupts cytoplasmic membranes of Gram-negatives;

• toxic to human kidneys

• Amphotericin B (polyene) attaches to ergosterol found in fungal membranes

• Humans somewhat susceptible because cholesterol similar to ergosterol

• Bacteria lack sterols; not susceptible

3. Disruption of Cytoplasmic Membranes


Disruption of Cytoplasmic Membranes


• When differences exist between metabolic processes of pathogen and host, anti-metabolic agents can be effective

• Metabolic antagonists

4. Inhibition of Metabolic Pathways


Inhibition of Metabolic Pathways


• Sulfonamides (Sulfa drugs)

• Inhibit folic acid synthesis

• Broad spectrum

Competitive Inhibitors

Figure 5.7



• Trimethoprim - binds to enzyme involved in conversion of dihydrofolic acid to THF

• Humans obtain folic acid from diet; metabolism unaffected

• Antiviral agents can target unique aspects of viral metabolism

• Amantadine, rimantadine, and weak organic bases neutralize acidity of phagolysosome and prevent viral uncoating

Inhibition of Metabolic Pathways


• Several drugs function by blocking DNA replication or mRNA transcription

• Only slight differences between prokaryotic and eukaryotic DNA;

• drugs often affect both types of cells

• Not normally used to treat infections;

• used in research and perhaps to slow cancer cell replication

5. Inhibition of Nucleic Acid Synthesis


• Compounds can interfere with function of nucleic acids (nucleotide analogs)

• Distort shapes of nucleic acid molecules and prevent further replication, transcription, or translation

• Most often used against viruses;

• viral DNA polymerases more likely to incorporate

• viral nucleic acid synthesis more rapid than that in host cells

• Also effective against rapidly dividing cancer cells

Inhibition of Nucleic Acid Synthesis




• Rifamycin

• Inhibits RNA synthesis (RNA polymerase)

• Antituberculosis

• Quinolones and fluoroquinolones

• Ciprofloxacin

• Inhibits prokaryotic DNA

• Urinary Tract Infections



• Prevention of Virus Attachment

• Attachment can be blocked by

• peptide and sugar analogs of attachment or receptor proteins (attachment antagonists)

• Still in developmental stage

6. Inhibition of Pathogen Attachment


Mechanisms of Antimicrobial Action


• Readily available

• Inexpensive

• Chemically stable

• Easily administered

• Nontoxic and nonallergenic

• Selectively toxic against wide range of pathogens

Ideal Antimicrobial Agent


• Spectrum of action

• Efficacy

• Dosages required to be effective

• Routes of administration

• Overall safety

• Side effects

Evaluation of Antimicrobial


Spectrum of Action


Diffusion Susceptibility Test


Routes of Immunization


• Topical - if infection is external

• Oral – simplest

• lower drug concentrations in blood

• no reliance on health care provider

• patients do not always follow prescribing information

• Intramuscular – requires needle for administration

• concentration never as high as IV administration

• Intravenous – requires needle or catheter

• drug concentration diminishes as liver and kidneys remove drug from circulation

• Must know how antimicrobial agent will be distributed to infected tissues

Routes of Immunization


• Three main categories of side effects

• Toxicity

• Allergies

• Disruption of normal microbiota

Safety and Side Effects


The Development of Resistant Organisms in Populations

• Some organisms are naturally, partially, or completely resistant

• Resistance by bacteria acquired in 2 ways

• New mutations of chromosomal genes

• Acquisition of R-plasmids via transformation, transduction, and conjugation


The Development of Resistant Organisms in Populations

Figure 10.15


• Pathogen can acquire resistance to more than one drug at a time

• Common when R-plasmids exchanged

• Develop in hospitals and nursing homes; constant use of drugs eliminates sensitive cells

• Superbugs

• Cross resistance

Multiple Resistance and Cross Resistance


• High concentrations of drug

• maintained in patient for long enough time

• to kill all sensitive cells

• and inhibit others long enough for immune system to destroy

• Use antimicrobial agents in combination

• synergism vs. antagonism

• Limit use of antimicrobials to necessary cases

• Development of new variations of existing drugs (novel side chains added to original molecule)

• Second-generation drugs

• Third-generation drugs

Retarding Resistance

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Antimicrobialsrms.rsccd.edu/faculty/KathyTakahashi/Bio229/ExamII...•no reliance on health care provider •patients do not always follow prescribing information •Intramuscular