Abstract
Gram-negative bacteria-producing extended-spectrum β-lactamases (ESBLs) are found to be truly multiresistant pathogens causing severe clinical problems. In our investigations, fifteen class C β-lactamases with extended substrate spectra have been reported in Gram-negative pathogens. Because of the emergence and dissemination of these enzymes, we propose that these enzymes be recognized as class C ESBLs (cESBLs), although most of the known ESBLs are class A and D β-lactamases. To decrease the selective pressure of antimicrobial drugs and minimize antimicrobial resistance, it is necessary for health-care professionals to recognize the presence of emerging cESBLs as a new and disturbing trend in antimicrobial resistance of Gram-negative pathogens. Because there is currently no drug development against cESBL-producing Gram-negative pathogens in progress and large pharmaceutical companies have largely withdrawn from research and development of new antimicrobial drugs, there is a tremendous need for the development of new β-lactams (or β-lactamase inhibitors) by focused cooperation between academia and small pharmaceutical companies, using the similar structural mechanism (a potential therapeutic target) of the extended substrate spectrum shown in most cESBLs. The consensus view about antimicrobial resistance is that severe clinical problems arise from the emergence of antibiotic resistance in Gram-negative pathogens causing nosocomial infections, and from the lack of new antimicrobial agents to challenge the threat [1]. There are four disturbing trends (extending substrate spectra) in the increasing antimicrobial resistance of Gram-negative pathogens [1]: (i) class B β-lactamases (metallo-β-lactamases) conferring resistance to almost all β-lactam antibiotics [2]; (ii) a bifunctional aminoglycoside-modifying enzyme [3]; (iii) the evolution of a fluoroquinolone-modifying enzyme from an aminoglycoside acetyltransferase [4]; and (iv) a new plasmid-borne fluoroquinolone efflux determinant [5]. These disturbing trends indicate that options for the treatment of health-care–associated Gram-negative infections are perilously limited as the organisms expand their ability to evade existing antimicrobial agents [1],[6]. Here we wish to draw attention to a new disturbing trend (the recently emerging class C extended-spectrum β-lactamases [ESBLs]), and to the antimicrobial drug development for class C ESBLs. We suggest also that the category of ESBLs has to be expanded.
Highlights
The consensus view about antimicrobial resistance is that severe clinical problems arise from the emergence of antibiotic resistance in Gram-negative pathogens causing nosocomial infections, and from the lack of new antimicrobial agents to challenge the threat [1]
In view of no drug developments against C ESBLs (cESBLs)-producing Gram-negative pathogens, new b-lactams or b-lactamase inhibitors need to be developed by the structure-based drug design (SBDD) method [25] using a similar mechanism of the extended substrate spectrum shown in most cESBLs
We propose that these enzymes be recognized as class C extended-spectrum b-lactamases (ESBLs)
Summary
ESBLs are defined as blactamases able to hydrolyze the penicillins, cephalosporins (first-, second-, and third-generation), and monobactams (aztreonam), but not the cephamycins or carbapenems [7]. Most of the known ESBLs are class A and D b-lactamases [7], but 15 class C b-lactamases with extended substrate spectra have been reported in Gram-negative pathogens isolated from clinical specimens of patients since the first description of GC1 in 1995 (Table 1). The cESBLs were first defined as follows: i) extended specificity class C blactamase for GC1 in 1995 [8]; ii) extended-spectrum AmpC-type b-lactamase for MHN-7.6 in 1998 [9]; iii) extended-spectrum class C b-lactamase for GC1 in 1999 [10]; and iv) extendedspectrum AmpC b-lactamase (ESAC) for CHE in 2001 [11]. Extended-spectrum class C (AmpC) b-lactamase can be designated class C extended-spectrum b-lactamase (cESBL). Most cESBL (13 of 15 natural cESBLs produced by Gram-negative pathogens isolated from clinical specimens of patients: SMSA, CHE, Ear, AmpCD, HD, EC14, EC15, EC17, EC19, CMY19, BER, 520R, and KL) have extended their substrate specificity to third- and fourth-generation cephalosporins (Table 1).
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