532 Lec 26-27

what drug

what drug

vancomycin

what drug

teicoplanin

ramoplanin looks like this

Talavancin (Vibativ), Dalbavancin, Chlorobiphenyl Vancomycin, Oritavancin,

Target bacteria cell wall synthesis

Transpeptidation inhibitors

bind directly to the D-alanyl-D-alanine termini of the peptidoglycan precursors.

Why are vancomycin, teicoplanin and ramoplanin effective only against gram positive

Microbes?

Vancomycin, teicoplanin, and ramoplanin are glycopeptide antibiotics effective against Gram-positive bacteria because they target the synthesis of the bacterial cell wall, specifically interfering with peptidoglycan formation

In contrast, Gram-negative bacteria have a different cell wall structure, preventing glycopeptide antibiotics from reaching their target.

2. Know how vancomycin (and by inference teicoplanin) inhibits both transpeptidases

and transglycosidases in numerous bacteria. Be able to show how different parts of

vancomycin interact with the peptide sequence D-ala, D-ala, L-lys and also what parts of

the molecule appear to mimic the NAG-NAM glycan part of the peptidoglycan

monomers when binding to transglycosidases.

it blocks it

Understand why the switching over of bacteria from using D-ala, D-ala, L-lys to D-lac,

D-ala, L-lys leads to a loss in activity of vancomycin. Bear in mind the importance of lost

H-bond but also introduced repulsive interactions between electron lone pairs on

vancomycin and the “new” D-lac, D-ala, L-lys binding partner. Know that in the case of

vancomycin how this translates to about a 1000-fold loss in binding affinity of

vancomycin for its target peptide sequence. Be able to provide a solution to the problem

just as we talked about in class with the replacement of a vancomycin amide with a

secondary amine.

ugh

Why are talavancin, dalbavancin, chlorobiphenyl vancomycin

& oritavancin better able to inhibit transglycosidase relative to

Vancomycin?

because they seem to bind better seems to correlate

to increased lipophilicity in the sugar binding components of vanco analogs.

structural differences between Talavancin (Vibativ – approved 2009) and vancomycin that lend talavancin a greater degree of antibacterial activity.

Talavancin, unlike vancomycin, has a lipophilic tail that helps it penetrate bacterial membranes more effectively. This, combined with its dual mode of action of inhibiting cell wall synthesis and disrupting membrane integrity, makes talavancin more potent against a wider range of Gram-positive bacteria

MraY and MurG enzymes roles in peptidoglycan monomer production

MraY and MurG are enzymes involved in peptidoglycan synthesis. MraY transfers the peptidoglycan precursor Lipid I to the bacterial membrane, while MurG adds N-acetylglucosamine to form Lipid II.

how MraY is inhibited by tunicamycin, muraymycin, and caprazamycin. What part of

these structures is isosteric with the key starting material to “Lipid I”?

Tunicamycin, muraymycin, and caprazamycin inhibit MraY by mimicking the nucleoside part of Lipid I, blocking its synthesis.

The nucleoside moiety in tunicamycin, muraymycin, and caprazamycin is isosteric with the key starting material for "Lipid I."

what drug

tunicamycin

what ramoplanin is, how it is similar and how it is dissimilar to vancomycin.

How does ramoplanin appear to demonstrate antibacterial activity?

→Possesses the same mechanism of action as Vancomycin

→Binds the entire Lipid-II/NAM-NAG unit:

Blocks trans-glycosylation and likely also trans-peptidation. Similar to Vanco in that it appears to be a dual inhibitor

→Ramoplanin is approved by FDA, but is unstable in the blood, can only be used orally

What drug and MOA

erythromycin (ketolides) MOA

etolide - bind 50S and blocks peptide exit tunnel → inhibits bacterial protein synthesis

tygacil

glycyclines - block entry of aminoacyl-tRNA into ribosome’s A site → inhibits bacterial protein synthesis

Whar drug and MOA

Imipenem

new carbapenems

• imipenem

• meropenem

• doripenem

• razupenem

carbapenems MOA

Beta-lactam MOA

fluoroquinolones

• ciprofloxacin

• levofloxacin

• finafloxacin

• JNJ-Q2 (still in trials)

fluoroquinolone MOA

bacterial DNA gyrase inhibitor → inhibits DAN replication

Fidaxomicin MOA

Inhibits bacterial RNA polymerase

Bedaquiline MOA

Bacterial ATP synthase proton pump inhibitor