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.