To develop a new class of

1
(No Transcript)
2
Objective
To develop a new class of broad spectrum
antibiotic based on bacterial quorum sensing.
3
Antibiotic Cellular Targets
Nucleotides sulfonamides Trimethoprim
Protein Synthesis Chloramphenicol Tetracycline Ery
thromycin aminoglycosides Zyvox
Cell Wall penicillins cephalosporins Bacitracin Va
ncomycin
Cell Membrane Polymyxin Colistin
DNA Gyrase quinolones
RNA Polymerase Rifampin
4
Quorum Targets
5
Quorum Sensing The Discovery

• Low cell density
• Low autoinducer concentration
• Luminescence pathways Off

6
Quorum Sensing The Discovery

• High cell density
• High autoinducer concentration
• Luminescence pathways ON

7
The LuxI/R SystemV. fisheri
O
OH
AI
O
O
N
O
O
OH
OH
O
O
O
O
N
N
luxI
luxR
Luciferase
8
Aberdeen
Nottingham
Norwich
Cambridge
Lausanne
McGill
Rochester
Marseille
Illinois
Princeton
Arizona
Iowa
New York
Maryland
Texas AM
Unam
New South Whales
9
The Peptide Quorum System
H
ABC transporter
D
Precursor
Target gene
10
The V. harveyi System

AI-1
AI-2
LuxN
LuxPQ
LuxU
H
LuxO
D
Luciferase
luxLM
luxS

Not actual AI-2
11
OM
LuxP
AI-2
IM
NH2
LuxQ
ATP
COOH
ADP
12
(No Transcript)