β-Lactamases continue to be the leading cause of resistance to β-lactam antibiotics among gram-negative bacteria. In recent years there has been an increased incidence and prevalence of extended-spectrum β-lactamases (ESBLs), enzymes that hydrolyze and cause resistance to oxyimino-cephalosporins and aztreonam.
Emergence of resistance to β-lactam antibiotics began even before the first β-lactam, penicillin, was developed. The first β-lactamase was identified in Escherichia coli prior to the release of penicillin for use in medical practice. The age of penicillin saw the rapid emergence of resistance in Staphylococcus aureus due to a plasmid-encoded penicillinase. This β-lactamase quickly spread to most clinical isolates of S. aureus as well as other species of staphylococci.
Figure 1. Extended-Spectrum β-Lactamases (ESBLs).
Beta-lactamases are enzymes produced by some bacteria and are responsible for their resistance to beta-lactam antibiotics like penicillins, cephamycins, and carbapenems (ertapenem) (Cephalosporins are relatively resistant to beta-lactamase). These antibiotics have a common element in their molecular structure: a four-atom ring known as a beta-lactam. The lactamase enzyme breaks that ring open, deactivating the molecule's antibacterial properties. Beta-lactam antibiotics are typically used to treat a broad spectrum of Gram-negative bacteria. Beta-lactamases produced by Gram-negative organisms are usually secreted.
Figure 2. Structure of a Streptomyces albus beta-lactamase.
Importance of β-lactamase induction
Induction of β-lactamase synthesis is important for the resistance of staphylococci to penicillins since the drug both induces synthesis of the enzyme and is hydrolysed by it. Similarly, some compounds both strongly induce and are hydrolysed by the chromosomally-determined β-lactamases of gram-negative bacilli (e.g. amoxicillin and cefoxitin for Enterobacter cloacae). Other compounds (e.g. piperacillin and cefotaxime) although labile are poor inducers, so that in the case of these drugs the phenomenon of induction is not important but the presence of the enzymes is, since resistant mutants with genetically derepressed synthesis of the enzyme can emerge. Induction can also be important when a strong inducer is present with a poor inducer and antagonises the activity of the latter.
Clinical importance of β-lactamase
Resistance to b-lactam-containing antimicrobial agents continues to increase, frequently due to the presence of b-lactamases in Gram-negative bacteria. Over the past twenty-five years broad-spectrum enzymes such as TEM- and SHV-variants and the metallo-b-lactamases have become more prolific. As a result of the ability of plasmids to continue to acquire additional resistance determinants, many of the b-lactamase-producing Gram-negative pathogens have become multi-drug resistant. In combination with decreased permeability, the organisms can become virtually untreatable with current therapies. The major groups of b-lactamases that pose the most serious therapeutic problems include the extended-spectrum b-lactamases, the plasmid-mediated cephalosporinases, the inhibitor-resistant TEM- or SHV-derived b-lactamases and the carbapenem-hydrolyzing b-lactamases.
Figure 3. Fluorescent detection of β-lactamase reporter gene response Fluorescent detection of β-lactamase reporter gene response Fluorescent detection of β-lactamase reporter gene responseFluorescent detection of β-lactamase reporter gene responcse.
Source: Extended-Spectrum β-Lactamases in the 21st Century: Characterization, Epidemiology, and Detection of This Important Resistance Threat, Patricia A. Bradford. Importance of beta-lactamase induction,I. Phillips and K. Shannon. beta-Lactamases of increasing clinical importance,Bush K. Wikipedia.
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