Gram-Negative Efflux Resistance

The situation is quite different for Gram-negative bacteria, some more than others, and in particular P. aeruginosa, the Gram-negative superbug. P. aeruginosa is a 

These considerations provide a strong argument and rationale for discovery and development of inhibitors of RND transporters from Gram-negative bacteria that could be used in conjunction vdth antibiotics. Such inhibitors would increase antibacterial potency, expand the spectrum of antibacterial activity, reverse resistance 

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Currently, five different molecular classes of mdr efflux pumps are known [5], While pumps of the the ATP-binding cassette (ABC) transporter superfamily are driven by ATP hydrolysis, the other four superfamilies called resistance-nodulation-division (RND), major facilitator superfamily (MFS), multidrug and toxic compound extrusion (MATE), and small multidrag resistance transporter (SMR) are driven by the proton-motive force across the cytoplasmic membrane. Usually a single pump protein is located within the cytoplasmic membrane. However, the RND-type pumps which are restricted to Gram-negative bacteria consist of two additional components, a periplasmic membrane fusion protein (MFP) which connects the efflux pump to an outer... 

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. 

Fig. 9.1 Schematic representation of possible mechanisms of resistance in Gram-negative and Gram-positive bacteria. 1, antibiotic-inactivating enzymes 2, antibiotic efflux proteins 3, alteration or duplication of intracellular targets 4, alteration of the cell membrane reducing antibiotic uptake 5, alterations in porins or lipopolysaccharide reducing antibiotic uptake or binding.

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. 

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. 

Chloramphenicol inhibits protein synthesis by binding the 50S ribosomal subunit and preventing the peptidyltransferase step. Decreased outer-membrane permeability and active efflux have been identified in Gram-negative bacteria however, the major resistance mechanism is drug inactivation by chloramphenicol acetyltransferase. This occurs in... 

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