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Chapter 15 : Active Drug Efflux in Bacteria
Category: Bacterial Pathogenesis
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The major facilitator superfamily (MFS) comprises drug-specific pumps like the tet- and otrB-encoded tetracycline transporters found in many gram-positive bacteria and gram-negative bacteria. The majority of macrolide-resistant pneumococci in the United States, Canada, South America, Hong Kong, Singapore, Thailand, and Malaysia were cases of mef-mediated resistance. Fluoroquinolone resistance in gram-negative bacteria due to target site alteration can be substantially supported by efflux. Multiple-antibiotic-resistant (mar) mutants of Escherichia coli have decreased outer membrane permeability due to reduced porin expression and at the same time show increased efflux. An interesting aspect of the VceC structure is that the resolved positions of two octyl-β-glucoside molecules were as expected for lipopolysaccharides (LPS) of the bacterial outer membrane. The majority of the multidrug and toxic compound extrusion family (MATE) transporters identified until now use the electro-chemical potential of Na+ across the membrane to drive multidrug export. Multidrug ABC transporters contribute to multiple antibiotic resistance in bacteria and cause multiple-cancer-drug resistance in humans. Apart from contributing to resistance against anticancer chemotherapy, drug efflux is highly relevant for the successful treatment of bacterial infections by tetracycline, macrolide, and fluoroquinolone antibiotics. NorA in S. aureus, PmrA in S. pneumoniae, and (clinically less relevant) Bmr and Blt in B. subtilis are clear examples of the high relevance of drug efflux for fluoroquinolone resistance in gram-positive bacteria. The MFS members CmlA and FloR specifically export chloramphenicol and the structurally related veterinary drug florfenicol. They confer inducible resistance in many gram-negative bacteria including P. aeruginosa, H. influenzae, and the Enterobacteriaceae.
Schematic representations of different drug efflux systems. The shapes depict major characteristics where known. More-detailed information about the topology, occurrence in different organisms, and function is given in the text and in Table 15.1 .
Three-dimensional structure of a MexA monomer from P. aeruginosa (Protein Data Base [PDB] code 1vf7).
Model for a tripartite AcrAB-TolC efflux system. The hypothetical collar-like structure of an AcrA multimer is indicated by the sketch, which overlaps the AcrB and TolC trimers. The boundaries of lipid bilayers are indicated as black lines.