Antibiotic Resistance: Modification or Destruction of the Antibiotic

In this chapter, we take up three cases of clinically important antibiotics in which modification or destruction of the antibiotic is a principal route to neutralization/inactivation of the antibiotic class (Fig. 10.0) (Walsh, 2000). The first deals with enzymatic hydrolysis of the β-lactam warhead in penicillins, cephalosporins, and carbapenems. The second deals with modification of each of the two streptogramin components of the Synercid combination, reflecting two different approaches to render the polyketide versus the nonribosomal peptide scaffold of streptogramin A and streptogramin B components unrecognizable by their intended ribosome targets. The third example involves the suite of enzymes known to modify sites in the tricyclic framework of aminoglycosides. Fourteen distinct sites on those antibiotics are targeted by three different kinds of group transfer enzymes that use either ATP or acetyl coenzyme A (acetyl-CoA), thermodynamically activated substrates of primary metabolism, to derivatize oxygen or nitrogen atoms. The addition of charged (phosphate, AMP) and/or bulky (AMP, acetyl) groups to the aminoglycosides disrupts high-affinity binding to the 16S rRNA sites on the 30S ribosomal subunit.