• History • Mechanisms • Clinical considerations •...
Transcript of • History • Mechanisms • Clinical considerations •...
Antimicrobials in vivo
• History • Mechanisms• Clinical considerations• Resistance
Vancomycin resistant Staphylococcus aureus
Antimicrobial Chemotheraputics
Antibacterials - synthetic or antibioticsAntifungals - syntheticAntiprotozoals - syntheticAntivirals - synthetic
Understand specificity and target - if described.
History - ALL Nobel Prize Winners
Ehrlich - father of chemotherapyLate 1800s chemist - “magic bullets”Synthetic arsenic-based “salvarsan”Targeted and killed syphilis bacterium
Fleming - 1928
• First true antibiotic -penicillin, more later
• Fungi Penicillium made compound that…
• Inhibited bacteria Staphylococcus
• But non-toxic to laboratory animals
• It would be a decade before biochemists figured out how to mass-produce penicillin
.
Domagk - 1935
Synthetic dye killed Staphylococcus in miceIn fact, dye converted to sulfanilamide in miceAnd “sulfa” was what killed bacteriaMANY other similar sulfa drugs now madeCompetitive inhibitor
Waksman - 1944
Second true antibiotic (he coined the word)
Soil bacteria Streptomyces made streptomycin
That inhibited hard-to-cure TB bacterium
Later found to inhibit broad array of bacteria
Mechanisms of Antibiotic Action
Cell Wall: Penicillin
• Halts assembly of bacterial wall - bacteriocidal• Narrow spectrum, against Gram Positives…lots of
peptidoglycan• - can’t pass LPS easily because of chemistry
Wall-specific Semi-synthetic drugsChemists add new side-groups to penicillinThese sometimes extend range - broadOr improve retention in the bodyExample - Amoxicillin, Ampicillin, Methicillin
MRSA = methicillin-resistant S. aureus
Inhibition of Protein synthesis
StreptomycinLook similar to part of
bacterial ribosomeEffects smaller ribosomes
of bacteriaPrevents translation in
bacteriaBroad spectrum and
bacteriocidal
Inhibit metabolic pathways
Sulfa DrugsLook similar to compound called PABAOnly BACTERIA convert PABA to folic
acidBacteriostatic, NOT bacteriocidalBroad spectrum - Gram Positive and
Negative
Inhibit nucleic acid synthesis
Ciprofloxacin - a synthetic drug
Look similar to bacterial DNA-binding proteins
Prevents bacterial replication, gene expression
Broad spectrum and bacteriocidal
Disrupt cell membrane
Polymyxin (made by soil Bacillus)Look similar to LPS membrane moleculesDisrupts LPS - affects Gram Negatives
moreNarrow spectrum and bacteriocidal
Clinical aspects of antimicrobial drugs
Ideal ChemotheraputicAntimicrobials…
Kill or inhibit pathogens - before multiply/mutate
Cause no damage to the host (selective toxicity)
Be stable in solid or liquid formRemain in body long enough to work
Spectrum of Activity
Broad vs narrow spectrum
Route of administration
• External: topical• Problems: removal by
kidney• Metabolism by liver• Blood-brain barrier• Allergies• Toxicity• Disruption of normal
microflora
Anti-Eukaryotic and Antiviral Drugs
Some General IdeasMore side effects - they are like us or…They rely on our machineryAll synthetic drugs made by chemistsLike antibacterials, all act on specific targets…
Antifungals
Unique fungal membrane lipids -miconazole
Halts rapid fungal DNA replication -flucytosine
Some Antiprotozoals and TargetsHalts DNA replication - chloroquine (Malaria)Halts metabolism - flagyl (Giardia)
Some Antiviral Drugs and TargetsDNA synthesis - Acyclovir (Herpes)*Retrovirus Enzymes - AZT (HIV)*Protein Assembly - Saquinavir (HIV)
*Also nucleotide analogs.
Antibiotic Resistance
Target binding site mutated - drug can’t bindMembrane becomes impermeable to drugNew enzyme that destroys drugNew pump that exports drug
Some bacteria have on chromosomes (intrinsic); others obtain onplasmids (acquired).
What Patients Can Do Not demand antibiotics for likely viral illnessTake ALL antibiotics as prescribedNot save extra antibioticsNot take them as a precaution (e.g. traveling)Avoid buying on-line or overseas with physicianPractice general prevention - hygiene, vaccines
What Health Care/Physicians Can Do Not give in when no evidence of bacteriaActually collect/test specimens for diagnosisIncluding testing for drug-resistanceChoose the RIGHT spectrum drugProvide exactly the correct amountPromote general prevention - hygiene, vaccines
All drugs have the potential to select for resistance… it boils down to evolution.