Antibiotic resistance efflux pump

EmrE is a multidrug resistance efflux pump with specificity to a wide range of antibiotics and antiseptics. To obtain atomic-scale insight into... 

Two mechanisms are operating alone or in concert to minimize the antibiotic concentration at the intracellular target site Downregulation of the expression of the pore proteins, also called porins, and upregulation of one or a set of several unspecific efflux pumps. However, the impact of these mechanisms on the resistance is low, since due to the essential function of porins for uptake of nutrients their reduction is limited and to avoid disturbances of membrane integrity due to extensive oveiproduction of mdr efflux pumps these are subjected a strict regulation. 

The combined intrinsic activities of different efflux pumps play a major role for the intrinsic resistance of Gram-negative bacteria to macrolides and oxazolidi-nones as well as to the intrinsic resistance of Pseudomonas aeruginosa against a broad range of disinfectants and antibiotics. 

In some cases, catechins can also act in synergistic mode when used in association with currently used antibiotic molecules (Table 2). EGCG exhibited synergy with /3-lactams. Sudano Roccaro et al. [73] found that this compound is able to reverse tetracycline resistance in Staphylococcus epidermidis and S. aureus isolates. This synergistic interaction has been explained by inhibition of tetracycline efflux pump activity in microbial cells resulting in an... 

Finally, some gram-negative organisms demonstrate a fourth mechanism of resistance. For example, strains of P. aeruginosa produce xenobiotic efflux pumps to eject antibiotics. Drug efflux mechanisms are associated with multiple drug resistance, including resistance to (3-lactam antibiotics. 

H Nikaido. Antibiotic resistance caused by gram-negative multidrug efflux pumps. Clin Infect Dis 27 Suppl 1 32 11, 1998. 

On the other hand, depsides are peptide analogs entirely build up by hydroxyl acids mutually connected through ester bonds. A representative example of depsides is the naturally occurring macrotetralide antibiotic nonactin (63). Nonactin has been shown to possess activity against the P170-glycoprotein efflux pump associated with multiple drug-resistant cancer cells. 

These mechanisms are of considerable microbiological and biochemical interest, although not all of the above agents find current use as biocides. The plasmid-mediated efflux pumps are particularly important, since efflux is one means whereby acquired resistance to antibiotics occurs (see earlier) and can be a mechanism of resistance to some clinically useful biocides (see later). No efflux pump comparable to those described for arsenate and cadmium [212] has yet been detected in silver-resistant bacteria [213] however, an up-to-date assessment of this subject is available [212]. 

Efflux pumps belonging to the resistance-nodulation-division (RND) family are especially effective in generating resistance and often have a wide substrate specificity. An extreme case is the AcrB pump of E. coli, which pumps out the antibiotics tetracychne, chloramphenicol, 6-lactams, novobiocin, fusidic acid, nalidixic acid and fluoroquinolones, as well as detergents, bile salts, various cationic dyes, disinfectants and even solvents. 

Although efflux is a daunting obstacle for many antibiotics, it is the balance between influx and efflux that determines whether cells will be sensitive or resistant in the face of an antibiotic challenge. As a result, reduced uptake of antibiotics coupled with activation of efflux pumps is a potent combination that can overcome sensitivity to drugs in many pathogens. 

Resistance has been reported so far in only a few enterococci isolated from immunocompromised patients treated with linezolid for long periods. The resistant isolates appeared to possess modified ribosomal RNA genes. Cross-resistance to other antibiotics has not yet been seen. Most Gram-negative bacteria are resistant by virtue of possessing membrane efflux pumps, but many obligate anaerobes are susceptible. 

Van Bambeke, F.B.E. and Tulkens, P.M. (2000) Antibiotic efflux pumps. Biochemical Pharmacology, 60, 457-470. Borst, P. and Ouellette, M. (1995) New mechanisms of drug resistance in parasitic protozoa. Annual Review of Microbiology, 49, 427-460. 

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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