Bacterial efflux pumps

The Major Facilitator Superfamily (MFS) [95-97] is the largest secondary transporter family known in the genomes sequenced to date [98], These polytopic integral membrane proteins enable the transport of a wide range of solutes, including amino acids, sugars, ions, and toxins. Medically relevant members of the family include the bacterial efflux pumps associated with... 

Bacterial efflux pumps have evolved as survival mechanisms for bacteria to reduce the internal concentration of noxious chemicals from their environment. These same pumps can expel antibiotics and other drugs used in the therapy of infections. 

Bokma. E., Koronakis, E., Lohedanz, S., Hughes, C., and Koronakis, V. (2006) Directed evolution of a bacterial efflux pump adaptation of the E. coli TolC exit duct to the Pseudomonas MexAB translocase. FEBS Letters, 580 (22), 5339-5343. 

Stavri, M., Piddock, L.J., and Gibbons, S. (2007) Bacterial efflux pump inhibitors fiom natural sources. The Journal of Antimicrobial Chemotherapy, 59 (6), 1247-1260. 

Kaatz, G.W. (2005) Bacterial efflux pump inhibition. Current Opinion in Investigational Drugs, 6 (2), 191-198. 

Spratt BG (1994) Resistance to antibiotics mediated by target alterations. Sdence 264 388-393 Stavri M, Piddock LJV, Gibbons S (2007) Bacterial efflux pump inhibitors from natural sources. J Antimicrob Chemother 59 1247-1260... 

Grapefruit oil is reported to have antibacterial activities. Its chromenone constituent has been shown to enhance antibiotic effect against MSSA and MRSA by acting as an inhibitor of the bacterial efflux pump mechanism. ... 

ATP-binding cassette (ABC) transporters are efflux pumps that derive the energy needed for drug extrusion from the hydrolysis of ATP. Bacterial ABC antibiotic efflux transporter encoded on plasmids is a significant... 

Cherigo L, Pereda-Miranda R, Fragoso-Serrano M, Jacobo-Herrera N, Kaatz GW, Gibbons S (2008) Inhibitors of Bacterial Multidrug Efflux Pumps from the Resin Glycosides of Ipomoea murucoides. J Nat Prod 71 1037... 

S pneumoniae, S aureus, H influenzae, Moraxella catarrhaiis, mycoplasmas, Legionella, Chlamydia, H pylori, N gonorrhoeae, fragilis, T gondii, and nontuberculosis mycobacteria. Many macrolide-resistant strains are susceptible to ketolides because the structural modification of these compounds renders them poor substrates for efflux pump-mediated resistance and they bind to ribosomes of some bacterial species with higher affinity than macrolides. 

An increased expression of efflux pumps, which prevents accumulation of the quinolone in the bacterial cell. Thus, the efflux pump NorA is responsible for the reduced sensitivity of S. aureus to hydrophilic fluoroquinolones such as norfloxacin, ciprofloxacin and ofloxacin, whereas quinolones such as sparfloxacin, trovafloxacin and moxifloxacin are not as greatly affected thereby. 

Copper ion homeostasis in prokaryotes involves Cu ion efflux and sequestration. The proteins involved in these processes are regulated in their biosynthesis by the cellular Cu ion status. The best studied bacterial Cu metalloregulation system is found in the gram-positive bacterium Enterococcus hirae. Cellular Cu levels in this bacterium control the expression of two P-type ATPases critical for Cu homeostasis (Odermatt and Solioz, 1995). The CopA ATPase functions in Cu ion uptake, whereas the CopB ATPase is a Cu(I) efflux pump (Solioz and Odermatt, 1995). The biosynthesis of both ATPases is regulated by a Cu-responsive transcription factor, CopY (Harrison et al., 2000). In low ambient Cu levels Cop Y represses transcription of the two ATPase genes. On exposure to Cu(I), CopY dissociates from promoter/operator sites on DNA with a for Cu of 20 jlM (Strausak and Solioz, 1997). Transcription of copA and copB proceeds after dissociation of CuCopY. The only other metal ions that induce CopY dissociation from DNA in vitro are Ag(I) and Cd(II), although the in vivo activation of copA and copB is specihc to Cu salts. The CuCopY complex is dimeric with two Cu(I) ions binding per monomer (C. T. Dameron, personal communication). The structural basis for the Cu-induced dissociation of CopY is unknown. Curiously, CopY is also activated in Cu-dehcient cells, but the mechanism is distinct from the described Cu-induced dissociation from DNA (Wunderh-Ye and Solioz, 1999). 

Higgins MK, Bokma E, Koronakis E, Hughes C, Koronakis V. Structure of the periplasmic component of a bacterial drug efflux pump. Proc. Natl. Acad. Sci. U.S.A. 2004 101(27) 9994-9999. 

Efflux is effectively the removal of an intracellular level of a biocide that would otherwise prove toxic to a bacterial cell. However, this has to be considered in the context of the actual concentration of biocide used. Whilst low levels of a biocide may be pumped out of a cell, at higher concentrations a competition would ensue between the damage inflicted on that cell and an efflux pump attempting to remove the toxic element. Under such circumstances, inactivation of the organism would occur rather than removal of the biocide. 

Nacsa et al. [153] confirmed that the MDR gene could be induced by different environmental stresses ( SOS gene ). The authors tested the inhibitory action of coordinating complexes of Cu(II) with TFZ and CPZ on megacin encoding bacterial gene induced by mitomycin C (MMC) as an example of SOS induction , and on the efflux pump of mouse lymphoma cells. The interaction... 

An enormous amount of information on bacterial efflux transporters has been summarized in several recent excellent review articles, addressing various aspects of the efflux problem, such as the origin and evolution of efflux pump [16], mechanisms of multidrug recognition [10,17], regulation of expression of MDR pumps [18-20], natural functions of MDR pumps [21], and clinical aspects of MDR [22-24]. 

MDR transporters are usually encoded by housekeeping genes as normal constituents of bacterial chromosome and are present in the whole population of a given bacterial species. The basal level of expression of nonspecific multidrug efflux pumps in wild-type cells determines the basal level of antibiotic susceptibility. This innate resistance may still be low enough such that bacteria are susceptible to therapy with a given antibiotic. 

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