Gram-Positive Efflux Resistance

pneumoniae. Inactivation of either of these transporters results in fourfold increased susceptibility [131, 132]. 

For the above reasons, a dramatic reduction in the emergence of fluoroquinolone (ciprofloxacin) resistance is seen when bacterial strains lacking efflux pumps are used for resistance selection or when selection experiments are performed in the presence of an efflux pump inhibitor (EPI) [133-136], the opposite of what is seen clinically. 

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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.

Resistance is increasing and may occur via T drug efflux or via changed sensitivity of the target enzymes—topoisomerase IV in the case of gram-positive cocci (e.g., staphylococci), topoiso-merase II in the case of E. coli, and increased efflux in the case of P. aeruginosa. 

Resistance to macrolides can result from (1) drug efflux by an active pump mechanism (2) ribosomal protection by inducible or constitutive production of methylase enzymes that modify the ribosomal target and decrease drug binding (3) macrolide hydrolysis by esterases produced by Enterobacteriaceae and (4) chromosomal mutations that alter a SOS ribosomal protein (found in B. subtilis, Campylobacter spp., mycobacteria, and gram-positive cocci). 

Telithromycin (ketek) is a semisynthetic derivative of erythromycin with modifications that render it less susceptible to methylase- and efflux-mediated resistance, increasing activity against many macrohde-resistant gram-positive strains. The structure of telithromycin is ... 

An ever-increasing range of gram-positive bacteria are being found to share a single mechanism of Cd resistance. The Cd " efflux P-type ATPase was first studied and sequenced in our laboratory (Nucifora et al. 1989 Silver et al. 1989). The CadA Cd ATPase of Staphylococcus is an outward-directed transport system whose synthesis is induced when resistant cells are exposed to Cd (Yoon et al. 1991 Tsai et al. 1992 Tsai and Linet 1993). Because the specifics of the CadA structure are considered again in Sect. D for comparisons with mammalian enzymes, some detail is appropriate at this point. 

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