BPS2110 Midterm 2 slides 3/4

antibiotics

selective poisons that target micrrobes

(bacteria, viruses, fungi, protozoa)

minimal effects to host

Why was salvarsan 606 a poor product

not soluble, not good dosing, slow, required 1 hour. administration inconvenient, weekly injections.

caused tissue necrosis

biological activity is STEP 1… subsequent steps regarding drug properties are more important

Prodrug vs active drug

1. Active drug

• Already pharmacologically active when administered.

• Can bind to its target (e.g., receptor or enzyme) and produce an effect directly.

• Does not need metabolic activation.

Example: Ibuprofen is administered in its active form and inhibits COX enzymes to reduce inflammation and pain.

2. Prodrug

• Administered in an inactive or less active form.

• Must undergo chemical or enzymatic conversion (usually through metabolism) to become pharmacologically active.

• The resulting active metabolite produces the therapeutic effect.

• attach a temporary group to improve absorption, once in blood steam group is enzymatically removed releasing active drug!

sulfonamides (sulfa drugs)

• bacteriostatic, inhibit bacterial growth and reproduction… DO NOT KILL BACTERIA

• dependent on patients competent immune system to eliminate bacteria

• mechanism: inhibit tetrahydrofolate synthesis

• bacteria need this to synthesize DNA, RNA,amino acids

sulfonamides resemble PABA (para-aminobenzoic acid) and compete for binding to the enzymes active site

if inhibitor binds, it cannot form product… so slows production

properties of competitive inhibitors

bind more tightly than the natural substrates

• nature does not make optimal systems, just good enough

• if biological systems were perfect drug therapy would be impossible

• humans will lack the target enzyme (so it doesnt affect them)

• we obtain tetrafolate from folic acid in food

PENICILLIN overview

• represent 80% of all antibiotics

• accidental discovery

Penicillin mechanism of action (draw also)

bacteria have a membrane bacterial cell wall (resists osmotic pressure, structure)

humans just have the membrane

As the bacteria grow, they expand their cell walls. Penicillin prevents the cell walls from forming properly during this expansion. As the cells grow, they therefore get "weak spots" in their cell walls. The existing pressure inside the cells causes the cells contents to burst through these weak spots. Like a hole in a balloon.

this works because the inside of the cell contains a high concentration of proteins, ions, and metabolites… this creates an osmotic gradient that drives water into cell

penicillin acts on the enzyme that creates cross links between poly peptide chains in the cell membrane! enzyme is needed to connect the chains.

osmotic pressure and cell stability

bacterial cells are very small, with high internal pressure, and require additional structure to contain pressure (cell wall)

the membrane prevents stuff from moving from inside to outside, but water from outside can easily move inside to reduce the concentration of stuff inside

moving water increases pressure inside cell, so with a poor cell wall, the cell will burst

DRAW

cytochrome P450 transformation

cell wall structure

cross linking?

D (rare in nature) and L amino acids (almost all natural amino acids have this configuration)

enzymatic amide hydrolysis

formation of new amide bond

transpeptidase

cell wall is made of long sugar strands (peptidoglycan strands) connected by short peptide chains

long sugar chain = horizontal, peptide cross links (connections holding them together)

transpeptidase is an enzyme that creates the connections between peptidoglycan strands

penicillin inhibits transpeptidase

more penicillin vs human cells

human cells lack cell walls and do not posess transpeptidase.

D-Ala-D-Ala linkag is unique to bacteria… all other amino acids have L configuration

Non toxic, few side effects, allergic reaction

source of allergy for penicillin

penicillin is a good electrophile, and can acylate host proteins to form abnormal conjugates

these tagged proteins are recognized as foreign by the immune system

penicillin G

isolated from mold

natural form of penicillin

major limitations: acid sensitivity, resistance, spectrum of action, bioavailability

penicillin complexity

penicillin core is complex and difficult to synthesize

strategy: obtain core from biological source, then modify it syntheticaly to create new derivatives

Resistance to penicillin

Many bacteria have developed resistance to penicillin. They evolve ways to get rid of the drug.

Mechanisms include: –

Mutations in transpeptidase –

Actively transport out of cell –

Enzymatic destruction of the drug

Beta lactamase:

also known as penicillinase

hydrolyze beta lactam ring (open it) inactivating drug

some bacteria product it to protect against penicillin

spectrum of activity

early penicillins were only active against grma positive stains

but we wanted them to work against both!!!

gram positive vs gram (negative draw )

• gram negative has an additional barrier for penicillin to cross

bioavailability of penicillin

some forms are poorly water soluble

Cephalosporins

has a beta-lactam

has 6 membered ring instead of 5

advantages: improved gram negative penetration and beta lactamase stability

resistance to beta lactamase due to reduced ring strain

disadvantages: not orally active, lower potency

also uses and was improved by semi synthetic modification

clavulanic acid

not an antibiotic: does not inhibit transpeptidase, does not kill bacteria…

inhibits beta lactamase!, preventing resistance to penicilllin

contains beta lactam

vancomycin

glycopeptide antibiotic

prevents cell wall cross linking

binds strongly to D-Ala-D-Ala, and blocks transpeptidase from accessing its substrate

STOPS cross linking (blocks it)