Current Topics of Molecular Life SciencesIOR- Prof. Dr. Matthias Ullrich

class presentationKedar 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), primary membrane transporter

glycerol-3-phosphate 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

• Efflux pump inhibitors taken with antibiotics

• Fluoroquinolone-resistant strains of E coli have been seen selected over wildtype (1000 fold).

AcrAB-TolC

Importance of efflux pumps in bacterial resistance

•MICs of antibiotics seen increased •Cross resistance, all generationsof 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 attention!! Reference

Francoise Van Bambeke, Elisabetta Balzi and Paul M. Tulkens (2000) Antibiotic Efflux Pumps, Biochemical Pharmacology, Vol. 60, pp. 457–470Satoshi 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 301Rungtip 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, Decemberhttp://saturn.med.nyu.edu/research/sb/wanglab/index.htmlhttp://en.wikipedia.org/wiki/Effluxhttp://opm.phar.umich.edu/?images=allhttp://whyfiles.org/038badbugs/mechanism.htmlhttp://focosi.altervista.org/gram+-bacteria.jpghttp://www.biotechnologyonline.gov.au/popups/img_antibiotics.cfmhttp://www.nearingzero.net/natural/screenres/natural095.jpg