hunting for panaceas
TRANSCRIPT
What would be the ideal activity for an anti-biofilm compound?
+ Compound X
Potent and Novel Anti-biofilm Compounds that Enhance Antibiotics (PaNACEAs)
Enhance tobramycin killing of P. aeruginosa biofilms
Tobramycin
• Aminoglycoside: binds to bacterial 30S ribosomal subunit impairing protein synthesis.
• Ototoxicity and nephrotoxicityCystic fibrosis
384 Pin tool + 384-well growth plate
Rinse plate
Treatment plate +250 mg/mL tobramycin (planktonic MIC-1 mg/mL)
Rinse plate
The PaNACEA Screening Protocol
BacTiterGlo
Summary of the pilot screen
Performed pilot screen of 6,080 biologically active compounds at the Center for Chemical Genomics.
Z-factor 0.6 (very good for actual biofilms!)
TRICLOSAN
• Colgate Total= 0.3% = 10 mM
• Mechanism of action: inhibits fatty acid synthesisfabI
• P. aeruginosa known to be resistant
CF11 CF13 CF78 CF99 CF101 CF144 CF1530
20
40
60
80
100
120
TriTobTri/Tob
P. aeruginosa CF Strain
Perc
ent B
iofil
m K
illin
g
Triclosan/Tobramycin effectively kills the biofilms of 19/19 clinical isolates tested
Before treatment
Tobramycin Triclosan Water To-bramycin+Tr
iclosan
P. aerugi-nosa
250000000 7611250 4928200 7391350 3860
3.2E+03
3.2E+04
3.2E+05
3.2E+06
3.2E+07
3.2E+08
CFU/mouse
Triclosan/Tobramycin effective in vivo
Future Directions
1. Screen the additional compounds libraries at the CCG
2. Identify mechanism of triclosan
3. Further characterize additional PaNACEAs
4. Move triclosan/tobramycin treatment forward
Waters LabAlessandra Hunt, PhDWill Soto, PhD
Eric BrugerNico FernandezMichael MaidenBen PursleyGeoff SeverinMeng ShiehRudy Sloup
Jake GibsonCharnay GlossJenny NybergJohn Shook
Alumni: Lauren Priniski!
CCG-University of MichiganMartha LarsenTom McQuadeDavid ShermanPamela SchultzCarl AverangAvi Raveh
Princeton UniversityMartin SemmelhakWei-wei LaoJiaqiang DongEric Kim