Current Topics of Molecular Life Sciences IOR- Prof. Dr. Matthias Ullrich class presentation Kedar Ghimire, May 15, 2007

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

Efflux pumps

Major superfamilies in prokaryotesMF (major facilitator, >1000) MATE (multidrug and toxic efflux) RND (resistance- nodulation- division) SMR (small multi-drug resistance)glycerol-3-phosphate transporter ABC (ATP binding cassette), primary 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. Colihttp://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

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Importance of efflux pumps in bacterial resistanceFINDINGS not evolved in response to antibiotics Increased expression linked with resistance but is not the only factor Intrinsic resistance of Gramnegative bacteria, e.g Pseudomonas aeruginosa Efflux pump inhibitors taken with antibiotics Fluoroquinolone-resistant strains

AcrAB-TolC

Importance of efflux pumps in bacterial resistanceMICs 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 conclusionIncreasing 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

Reference

Thank you all for your kind attention!!

Francoise Van Bambeke, Elisabetta Balzi and Paul M. Tulkens (2000) Antibiotic Efflux Pumps, Biochemical Pharmacology, Vol. 60, pp. 457470 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, DaNeng Wang (2003), Structure and Mechanism of the Glycerol-3Phosphate 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