Medchem material (2.2.7, 2.2.10, 2.2.12)

Penicillin G (fungal origin)

Cephalosporin C (fungal origin)

Thienamycin (bacteria origin (carbapenems))

Beta lactam antibiotics target ______, leading to inhibition of cell wall synthesis.

PBPs (transamidase)

Beta-lactam antibiotics are _________ agents

bactericidal (bacteria killing)

Beta lactam functional group characteristics

Electrophilic carbon

Beta-lactam antibiotics bind ____________ to the enzyme _______________, inhibiting bacterial wall synthesis

irreversible; transpeptidase

OH group from transpeptidase enzyme acts a ______________ oxygen and attacks the ________ carbon on the beta-lactam

nucleophilic; electrophilic

Bacterial resistance is due to __________, which inactivates the beta lactam

beta-lactamases (opens the ring)

Penam ring

Removing the steric bulk from the amide, makes the antibiotic _____________

more sensitive to beta-lactamase

Examples of molecules sensitive to beta-lactamase (removal of bulk)

Cefem ring

Carbapenem pharmacophore (SAR)

Carbapenem ring

Dimerization

On carbapenem antibiotics, for example thienamycin, ________________ is problematic for stability

free amine

Aminoglycosides inhibit protein synthesis by _______________, but there are likely several mechanisms of death ocuring.

binding to 30S ribosomal subunit

Streptomycin

Kanamycin

Blue: Amino

Purple: glycosides

Glycosidic bonds

Hexanose sugar moiety

Carbocycle

Disaccharide (2 sugar moeities together)

Aminoglycosides bond via ___________ to target proteins

hydrogen bonding

How do bacteria inactivate aminoglycoside antibiotics?

Using aminoglycoside modifying enzymes (AME)

What are the 3 aminoglycoside modifying enzymes (AME)?

1. Aminoglycoside acetyltransferase (AACs)

2. Aminoglycoside Phosphotransferases (APHs)

3. Aminoglycoside Nucleotidyltransferases (ANTs)

Alcohols and amines have lone pairs of electrons and have ____________

nucleophilic character

Aminoglycosides attack (nucloephile) the AME, which will transfer a group and ___________, which leads to inactivation.

remove the possibility of hydrogen bonding to the protein

What happens if you mix a beta-lactam with an aminoglycoside?

they will react with each other, inactivating themselves

Nalidixic acid

Ciprofloxacin

Fluoroquinolones (FQs) work by __________, inhibiting DNA replication

binding to DNA gyrase-DNA complex

FQs are _______agents

bactericidal

FQs are considered ____________ because of synthetic origin

antibacterial agents

Quinolone

Cell wall penetration (Potency)

A?

Pharmacophore

B?

Substitution interferes with binding

C?

potency

D?

Spectrum of activity

E?

Quinolone core is important for metal chelation, which helps bind DNA gyrase and topoisomerase IV

FQs kill bacterial cells by increasing the concentration of _________________

enzyme-DNA cleavage complexes

Quinolone-topoisomerase binding is facilitated through ____________

a water-metal ion bridge

Mechanisms of Fq resistance

1. Porin channels (in gram neg)

2. Plasmid-mediated resistance

3. Efflux pumps

4. Enzyme inactivation

5. Target modification

True or false: Aminoglycosidase acetyltransferase acylation can decrease the activity of Fluoroquinolones.

True

Mutations in gyrase and topo IV _______________

weaken quinoline-enzyme interactions