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Current Topics of Molecular Life Sciences

IOR- Prof. Dr. Matthias Ullrich


class presentation
Kedar Ghimire,
May 15, 2007
Efflux
pumps
• Efflux refers to the outward flow.

• Efflux pumps are protein


transporters
localized in the cell membrane.

• Active transport

• Found in bacteria as well as


eukaryotes (Bambeke et. al,2000)

•Specific or non-specific
Major superfamilies in
prokaryotes
•MF (major facilitator, >1000)

•MATE (multidrug and toxic efflux)

•RND (resistance- nodulation- division)

•SMR (small multi-drug resistance)

•ABC (ATP binding cassette), primaryglycerol-3-phosphate transporter


membrane transporter
Diagrammatic representation of the membrane topology of drug
transporters belonging to the ABC superfamily

Biochemical Journal Biochem. J. (2003) 376, 313-338


Resistance-nodulation-cell division transporter in
E. Coli

http://opm.phar.umich.edu/?images=all
Antibiotic resistance: what is it?
• One of the world's most pressing public health
problems.

• Nearly all significant bacterial infections in the


world are becoming resistant, genetic material
clonal

http://www.public.asu.edu/~shaydel/personnel.html
Importance of efflux pumps in
bacterial resistance
FINDINGS
• not evolved in response to
antibiotics

• Increased expression linked with


resistance but is not the only
factor

• Intrinsic resistance of Gram-


negative bacteria, e.g
Pseudomonas aeruginosa AcrAB-TolC

• Efflux pump inhibitors taken with


antibiotics

• Fluoroquinolone-resistant strains
Importance of efflux pumps in
bacterial resistance
•MICs of antibiotics seen
increased

•Cross resistance, all


generations
of antibiotics effected- a problem

•Expression increases with


stress. Over expression results
from mutation or activation

•Unregulated overexpression is

disadvantageous
Discussion and conclusion
•Increasing evidence about role
of efflux pumps in antibiotic
resistance

•Efflux pumps possess


significant structural homology

•Considerations for design of


new drugs
-structural alterations after
entrance into the cell

•Careful inhibition of pumps


necessary

•Researchers should be careful


Thank you all for your kind
Reference
attention!!
Francoise Van Bambeke, Elisabetta Balzi and Paul M. Tulkens
(2000) Antibiotic Efflux Pumps, Biochemical Pharmacology, Vol. 60, pp.
457–470
Satoshi Murakami, Ryosuke Nakashima, Eiki Yamashita & Akihito
Yamaguchi(2002) Crystal structure of bacterial multidrug efflux
transporter AcrB, Nature, 419(6907):587-93
Yafei Huang,M. Joanne Lemieux,Jinmei Song, Manfred Auer, Da-
Neng Wang (2003), Structure and Mechanism of the Glycerol-3-
Phosphate Transporter from Escherichia coli, Science, Vol 301
Rungtip Chuanchuen et al.,(2001) Cross-Resistance between Triclosan
and Antibiotics in Pseudomonas aeruginosa Is Mediated by Multidrug
Efflux Pumps: Exposure of a Susceptible Mutant Strain to Triclosan Selects
nfxB Mutants Overexpressing MexCD-OprJ, Antimicrobial Agents and
Chemotherapy, p. 428-432
Waltzing transporters and the dance macabre’ between humans
and bacteria(2007) Nature Reviews Drug Discovery, December
http://saturn.med.nyu.edu/research/sb/wanglab/index.html
http://en.wikipedia.org/wiki/Efflux
http://opm.phar.umich.edu/?images=all
http://whyfiles.org/038badbugs/mechanism.html
http://focosi.altervista.org/gram+-bacteria.jpg