ANTIMICROBIAL DRUGS



ANTIMICROBIAL DRUGS

Chapter 20

CHEMOTHERAPY

Use of drugs to treat diseases

Inhibit growth or kill the pathogen

Used internally, not externally like disinfectants

GOAL: Kill pathogen and do not harm the host

SELECTIVE TOXICITY

THREE CLASSES

ANTIBIOTICS - naturally produced by bacteria & fungi

SYNTHETIC DRUGS - synthesized in a lab

ANTI-VIRAL DRUGS

HISTORY #1

1910: Paul Ehrlich --> “MAGIC BULLET”

Some dyes stain eukaryotes & prokaryotes differently

POISON + DYE ----> Kill microorganism

ARSENIC & its derivatives --> SALVARSAN

SALVARSAN effective vs syphilis (T. pallidum)

1928: Alexander Fleming ---> PENICILLIN

S. aureus did not grow near the mold Penicillium notatum

P. notatum inhibitory substance secreted was toxic

“Penicillin” was unstable ----> discarded idea

ANTIBIOTIC from ANTIBIOSIS ie against life

HISTORY #2

1930s: Sulfa drugs were discovered

Prontosil ---> metabolized to SULFANILAMIDE

1940: Florey & Chain --> resumed penicillin studies

Isolated and purified penicillin

USA became involved and purified high-producing strains

Able to increase the stability of penicillin

Was used during WWII ---> “AGE OF ANTIBIOTICS”

ANTIBIOTICS

A substance that is produced by one microorganism (a bacterium or fungus) which in small amounts will kill or inhibit the growth of another microorganism

MAJOR PRODUCERS - most are soil organisms

MOLDS

Penicillium

Cephalosporium

BACTERIA

Streptomyces

Bacillus

SPECTRUM of ANTIMICROBIAL ACTIVITY

SELECTIVE TOXICITY

Drug should only kill/inhibit the pathogen not the host

DIFFERENCES BETWEEN PATHOGEN & HOST

Eukaryote host vs prokaryote pathogen

Eukaryote host vs eukaryote pathogen

Eukaryote host vs viruses

NARROW SPECTRUM

Effective only against Gram +ve OR Gram -ve bacteria

BROAD SPECTRUM

Effective against both Gram +ve AND Gram -ve bacteria

Normal flora may also be affected

PROPERTIES of ANTIBIOTICS

Antibiotics should be:

Selectively toxic

Bactericidal vs bacteriostatic

No resistance to the drug emerging

Broad spectrum of activity

No toxic side effects

Active in vivo (in the body)

Active at low concentrations

MECHANISMS of ACTION

INHIBIT CELL WALL SYNTHESIS

INHIBIT PROTEIN SYNTHESIS

INJURE PLASMA MEMBRANE

INHIBIT NUCLEIC ACID REPLICATION & TRANSCRIPTION

INHIBIT METABOLITE SYNTHESIS

1. INHIBITION of CELL WALL SYNTHESIS

Excellent selective toxicity

Peptidoglycan found only in prokaryotes

Penicillins & cephalosporins

Prevent cross linking of peptidoglycan units ∴ stops new cell wall synthesis

More effective against Gram +ve organisms

Bacitracin & vancomycin

Also inhibit cell wall synthesis

2. INHIBITION of PROTEIN SYNTHESIS

DIFFERENT RIBOSOME STRUCTURE

Eukaryotes = 80S (40S + 60S)

Prokaryotes = 70S (30S + 50S)

Mitochondrial = 70S

Bind to 50S subunit

Chloramphenicol - inhibits peptide bond formation

Erythromycin - prevents movement along mRNA

Bind to 30S subunit

Tetracyline - prevents tRNA attachment to ribosome

Streptomycin - changes shape of 30S ∴ reads mRNA incorrectly

3. INJURY to PLASMA MEMBRANE

Bind to and alter membrane permeability and/or cause leakage

Polypeptide antibiotics - polymxyin B

Antifungal drugs bind to membrane sterols and disrupt the membrane

Fungal cell membranes contain ergosterol

Animal cell membranes contain sterol

Examples

Ketoconazole & Miconazole

Amphotericin B & Nystatin

May be toxic to the host

4. INHIBITION of NUCLEIC ACID

REPLICATION and TRANSCRIPTION

Selective toxicity is POOR

STOP DNA replication

Many antiviral drugs act at this level

STOP RNA synthesis

5. INHIBITION of ESSENTIAL

METABOLITE SYNTHESIS

Many act as competitive inhibitors of enzymes

Drug mimics normal substrate (metabolite)

Enzyme binds drug and is inhibited

Pathway stops, normal metabolites are not produced

Example

Sulfanilamide (a sulfa drug) replaces PABA (para-aminobenzoic acid) a substrate in the folic acid pathway

Selectively toxic for microbes that synthesize PABA

Humans do not synthesize PABA

INHIBITORS of CELL WALL SYNTHESIS

ANTIBACTERIAL DRUGS

Penicillins

Cephalosporins

1. PENICILLINS #1

All have similar structure - “Penicillin nucleus”

Beta lactam ring = 4 member ring

Thiazolidine ring = 5 member ring with N & S atoms

Together these rings are called 6-aminopenicillanic acid

Unique side chain group that differentiates the different penicillins (R group)

Bactericidal - stops cell wall synthesis

Binds to a transpeptidase --> prevents crosslinking of peptides of peptidoglycan

Some are produced naturally

Some are produced semi-synthetically

1. PENICILLINS #2

R group affects

Spectrum of penicillin

pH stability

Sensitivity to penicillinase

Penicillinase (β-lactamase)

Enzyme that breaks down β-lactam rings

Secreted by some microorganisms

Alters activity of the penicillin

Many people may have allergic reactions and anaphylactic shock to Penicillins

NATURAL PENICILLINS

Penicillin G = prototype

Effective vs Gram positive bacteria

Staph & strep as well as gonoccoci and some spirochetes

Sensitive to low pH ∴ not taken orally

Often given with other drugs to increase retention time

Procaine and benzathine (I.M. injection)

Penicillin V - acid stable

Given orally

Both susceptible to penicillinase

Relatively narrow spectrum of activity

SEMISYNTHETIC PENICILLINS

Produced two ways:

Grow Penicillium so only the nucleus is produced then attach R group in the lab OR 2. grow Penicillium, extract the natural penicillin, remove the “natural” R group & replace with new R group

Tend to have a broader spectrum of activity

Effective vs Gram -ve bacteria as well (methicillin & oxacillin)

Aminopenicillins: ampicillin & amoxicillin

Resistance has developed against these

Carboxypenicillins: carbenicllin & ticarcillin

More effective vs Gram –ve & some P. aeruginosa sp.

Mix with clavulanic acid that inhibits penicillinase

Amoxicillin + clavulanic acid = Augmentin

3. CEPHALOSPORINS

Similar in structure and range of activity to penicillins

Inhibit prokaryotic cell wall synthesis

Relatively resistant to penicillinases

More effective vs some Gram -ve bacteria

Not sensitive to pH changes

First generation cephalosporins are active vs Gram +ve bacteria

EXCEPT: MRSA - methicillin resistant S. aureus

2nd and 3rd generation cephalosporins have a broader range of activity

Can have allergic reaction and superinfections

IINHIBITORS of PROTEIN SYNTHESIS

ANTIBACTERIAL DRUGS

Aminoglycosides

Tetracyclines

Chloramphenicol

Macrolides

1. AMINOGLYCOSIDES

Bactericidal - stop protein synthesis by binding to the 30S ribosomal subunit

Effective vs Gram -ve & some mycobacteria

STREPTOMYCIN - discovered in 1944

Alternative treatment for tuberculosis

Side effect --> damages 8th cranial nerve --> loss of hearing

GENTAMICIN

Effective vs Pseudomonas infections

NEOMYCIN

Used topically

Side effects: Hearing loss and kidney damage

2. TETRACYCLINES

Produced by Streptomyces

Very broad spectrum antibiotic

Gram +, Gram -, rickettsia & chlamydia

Bacteriostatic - inhibits protein synthesis

Many derivatives - oxytetracycline, chlorotetracycline

Doxycycline, minocycline, clorotetracycline

Used to treat urinary tract infections (UTI), chlamydial and spirochetal diseases

Can lead to GI upset & superinfections

Long term use ( tooth discoloration & kidney damage

Not used in pregnant women or young children

3. CHLORAMPHENICOL

Broad spectrum antibiotic

Bacteriostatic - inhibits protein synthesis

Binds to the 50S ribosomal subunit ( stops elongation of the protein

Small molecule ∴ diffuses readily (brain, CSF etc)

Used to treat meningitis & typhoid fever

Can suppress the bone marrow activity ( aplastic anemia

4. MACROLIDES

LARGE molecules

Contain a macrocyclic LACTONE RING

Bacteriostatic - inhibits proteins synthesis

Binds to the 50S subunit

ERYTHROMYCIN

Fairly narrow spectrum

Not very effective against Gram -ve

Alternate to penicillin (allergic patients)

Used to Legionella, Neisseria & mycoplasmas

Newer macrolides include

Azithromycin and clarithromycin

INJURY to PLASMA MEMBRANE

ANTIBACTERIAL DRUGS

Polymyxin B

ANTIFUNGAL DRUGS

Polyenes

Imidazoles and Triazoles

1. POLYMXIN B

Polypeptide antibiotic

Produced by Bacillus

Bactericidal - injures plasma membrane

Primarily effective vs Gram -ve bacteria

Used topically due to high toxicity

2. POLYENES

Antibiotic produced by Streptomyces

Fungicidal - interacts with membrane ergosterols to destroy selective permeability leading to death of the fungi

NYSTATIN

Treat localized fungal infections in the vagina and skin such as Candida albicans

AMPHOTERICIN B

Treat systemic fungal infections such as histoplasmosis but nephrotoxic

3. IMIDAZOLES & TRIAZOLES

Inhibit synthesis of ergosterols ∴ interferes with fungal growth

Used to treat dermatophytes, dimorphic fungi & yeasts

IMIDAZOLES

Clotrimazole and miconazole – used topically

Cutaneous mycoses (Athlete’s foot, vaginal yeast infections)

Ketoconazole – given orally (systemic mycoses)

TRIAZOLES

Fluconazole & itraconazole (Diflucan)

Less toxic, used to treat systemic and opportunistic infections

INHIBITORS of NUCLEIC ACID SYNTHESIS

ANTIBACTERIAL DRUGS

Quinolones and fluoroquinolones

Rifamycins

ANTIVIRAL DRUGS

Very few available, ANTIBIOTICS do not act on viruses

Often given to treat secondary bacterial infections

SELECTIVE TOXICITY = DIFFICULT

Usually numerous side effects

Amantadine

Ribavarin

Acylcovir

Ganciclovir

Idoxuridine and fluridine

Zidovudine (AZT)

3. AMANTADINE

First antiviral to be approved

A tricyclic amine

MECHANISM of ACTION

May prevents virus from entering the cell OR

May prevent uncoating of the virus after enters the cell

Effective against prevention of influenza A viruses

Usually used in the elderly to prevent spread of the disease

Especially in nursing homes & institutions to prevent spread of infection

Not effective once the disease has been contracted

Many side effects

5. ACYCLOVIR

ACYCLOVIR (Zovirax) - guanine analog

Used to treat herpesviruses infections

Genital herpes, chickenpox and shingles

Reduces pain & promotes healing of primary lesions in a new case of genital herpes

BASE ANALOG - structurally similar to nucleic acid bases

Stops viral DNA synthesis

Activated by a herpesvirus enzyme − herpesvirus specific

Can be administered as an ointment, orally or by injection

8. ZIDOVUDINE (AZT)

AZIDOTHYMIDINE (AZT) - thymidine analog

Stops the RNA dependent DNA polymerase of HIV

Reverse transcriptase

Used to treat AIDS patients

Sides effects = immunosuppression and anemia

Other nucleoside analogs used to block RT

Dideoxyinosine (ddI)

Dideoxycytosine (ddC)

INHIBITORS of ESSENTIAL METABOLITES

ANTIBACTERIAL DRUGS

Sulfonamides

1. SULFONAMIDES

1 of 1st synthetic drugs used to treat infections

Discovered in the 1930s

Bacteriostatic: interferes with folic acid synthesis

Folic acid needed for synthesis of purines & pyrimidines

Sulfanilamide similar to PABA (para-aminobenzoic acid)

Sulfanilamide is an ANTIMETABOLITE

Sulfamethoxazole usually given with trimethoprim as TMP-SMZ

Sulfamethoxazole – inhibits formation of dihydrofolate

Trimethoprim – inhibits synthesis of tetrahydrofolate

Usually effective vs Gram –vs M/O

Especially in urinary tract infections

TEST of CHEMOTHERAPY EFFECTIVENESS

Several different techniques have been developed

Disk-diffusion technique

Kirby Bauer Technique = standardized method

Pure culture of pathogen on agar plate

Paper discs containing antibiotic on agar plate

Incubate plates

Observe ZONES of INHIBITION of GROWTH

Automated systems also exist

DRUG RESISTANCE

One of the most serious threats affecting the world today.

Mechanisms of resistance:

Alteration of drug target inside the cell

DNA mutation leads to change in target

Usually affects ribosomes, drug can no longer bind.

Alteration of membrane permeability

Prevention of entry of drug into the cell

Change a membrane transport protein or increase ability to pump out of the membranes

Inactivation of the drug by enzymes.

Penicillinases or β lactamases.

. 4. Alteration of an enzyme, so a metabolic pathway is no longer affected by the drug.

How Resistance Occurs

Bacteria may become resistant to drugs through: genetic changes.

Antibiotics do not induce mutations but create environments that favors the resistant bacteria to grow.

MUTATION creating a resistant strain that will eventually be the only type of bacterium in the host. Change in bacterial chromosome. Usually causes resistance to one type of antibiotic.

ACQUIRING A PLASMID (R factors). Some can carry as many as six or seven genes for resistance to many classes of different antibiotics. Transferred from one strain and one species to another by conjugation or transduction.

How is Resistance promoted?

Overuse and misuse of antibiotics. Selective pressure.

Patient non compliance

Use of bacteriostatic drugs. Need to use drugs that are bacteriocidal and at concentrations that are high enough to kill most bacteria.

Use of antibiotics in animal feeds. Promotes transfer of resistant bacteria from animal to humans.

Limiting Drug Resistance

Responsibility of healthcare workers to target causative agent, identify it and treat it appropriately.

Patient compliance.

Decreasing or banning antibiotic use in animal feeds.

Administer a narrow spectrum antibiotic to treat specific organism.

Use of multiple drugs together.

SIGNIFICANCE of DRUG RESISTANCE

Resistant cells may make up a small percentage of the population

Resistant cells may be able to overgrow once sensitive cells in the population die

RESULT - large number of resistant cells

So drugs should not be used indiscriminately

Used at optimal concentrations/strengths

................
................

In order to avoid copyright disputes, this page is only a partial summary.

Google Online Preview   Download