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Enzymatic Destruction or Modification of the Antibiotic by Resistant Bacteria, Page 1 of 2
< Previous page Next page > /docserver/preview/fulltext/10.1128/9781555817886/9781555818937_Chap08-1.gif /docserver/preview/fulltext/10.1128/9781555817886/9781555818937_Chap08-2.gifAbstract:
Enzymatic inactivation of antibiotics occurs with several of the natural product antibiotic classes but has not yet been observed as a major route of resistance development for the classes of synthetic antibacterials: the sulfamethoxazole-trimethoprim combination, the fluoroquinolones, or the oxazolidinones. The most widespread mode of clinical resistance development to β-lactam antibiotics is the expression of β-lactamases that hydrolyze the antibiotic. Two approaches have been taken in the decades since lactam-resistant clinical isolates began to diminish the efficacy of penicillins and cephalosporins as antibiotics. The first has been to develop semisynthetic β-lactams which were slower substrates for attack by the hydrolytic lactamases. The second approach has been to screen for inhibitors and inactivators of lactamase activity and then combine these molecules with a β-lactam. β-Lactamase genes can be embedded in bacterial chromosomes, such as the ampC gene in enteric bacteria or the blaZ gene in Staphylococcus aureus, or they can be carried on multiple-copy plasmids or transposons, as is the case for the TEM-1 bla gene in a variety of high-level penicillin-resistant gram-negative bacteria found in clinical isolates. In Escherichia coli the ampG, ampD, and ampR genes control expression of the ampC-encoding β-lactamase. In S. pneumoniae external penicillin leads to an increase in autolytic peptidoglycan hydrolase activity and subsequent vulnerability to osmotic lysis and death. Three kinds of enzymatic modifications of OH and NH2 groups on aminoglycosides are common determinants of resistance and represent variants of normal electrophilic group transfer enzymes that participate in primary metabolism.