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
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