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Chapter 10 : Antibiotic Resistance by Replacement or Modification of the Antibiotic Target
One of the routes to clinically important resistance in pathogenic bacteria is the ability of drug-resistant pathogens to modify the drug target to insensitivity while still retaining its essential cellular function. This chapter exemplifies the principles of antibiotic resistance arising from replacement or modification of the target. This can be achieved by mutation at one or more sites in the target gene or by importation of a gene that specifies a new replacement enzyme that has markedly decreased sensitivity to the drug. β-lactam resistance in the grampositive Streptococcus pneumoniae and Staphylococcus aureus strains represent these two variations on a theme. Unlike the S. aureus strains and many other pathogens, S. pneumoniae does not use β-lactamases as the major route to penicillin resistance. Analysis of transpeptidases/transglycosylases in S. pneumoniae reveal five high-molecular-weight PBPs which contribute to killing by β-lactams. One of the goals of medicinal chemistry in developing broad-spectrum erythromycin family of macrolides is to overcome the Erm phenotypes by creating semisynthetic or altered versions of the macrolides that can still bind to methylated A2058 versions of the 23S rRNA. Telithromycin has recently been approved for human use and ABT-773 is in advanced clinical evaluation. Enterococcus faecalis species account for about 90 to 95% of vancomycin-resistant clinical isolates and E. faecium another 5%, with minor species accounting for the rest. There had been few therapeutic choices for vancomycin-resistant enterococci (VRE) treatment, but the recent approvals of both the Synercid combination and the oxazolidinone linezolid indicate efficacy against VRE.