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Carbapenem resistance in Elizabethkingia meningoseptica is mediated by metallo-?-lactamase BlaB.

ABSTRACT: Elizabethkingia meningoseptica, a Gram-negative rod widely distributed in the environment, is resistant to most ?-lactam antibiotics. Three bla genes have been identified in E. meningoseptica, coding for the extended-spectrum serine-?-lactamase CME (class D) and two unrelated wide-spectrum metallo-?-lactamases, BlaB (subclass B1) and GOB (subclass B3). E. meningoseptica is singular in being the only reported microorganism possessing two chromosomally encoded MBL genes. Real-time PCR and biochemical analysis demonstrate that the three bla genes are actively expressed in vivo as functional ?-lactamases. However, while CME elicits cephalosporin resistance, BlaB is the only ?-lactamase responsible for E. meningoseptica resistance to imipenem, as GOB activity is masked by higher cellular levels of BlaB. On the other hand, we demonstrate that bla(BlaB) expression is higher in the stationary phase or under conditions that mimic the nutrient-limiting cerebrospinal fluid colonized by E. meningoseptica in human meningitis.

SUBMITTER: Gonzalez LJ

PROVIDER: S-EPMC3318372 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Carbapenem resistance in Elizabethkingia meningoseptica is mediated by metallo-β-lactamase BlaB.

González Lisandro J LJ Vila Alejandro J AJ

Antimicrobial agents and chemotherapy 20120130 4

Elizabethkingia meningoseptica, a Gram-negative rod widely distributed in the environment, is resistant to most β-lactam antibiotics. Three bla genes have been identified in E. meningoseptica, coding for the extended-spectrum serine-β-lactamase CME (class D) and two unrelated wide-spectrum metallo-β-lactamases, BlaB (subclass B1) and GOB (subclass B3). E. meningoseptica is singular in being the only reported microorganism possessing two chromosomally encoded MBL genes. Real-time PCR and biochemi ...[more]

PMID: 22290979

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Project description:Production of metallo-β-lactamases (MBLs), which hydrolyze carbapenems, is a cause of carbapenem resistance in Enterobacteriaceae Development of effective inhibitors for MBLs is one approach to restore carbapenem efficacy in carbapenem-resistant Enterobacteriaceae (CRE). We report here that sulfamoyl heteroarylcarboxylic acids (SHCs) can competitively inhibit the globally spreading and clinically relevant MBLs (i.e., IMP-, NDM-, and VIM-type MBLs) at nanomolar to micromolar orders of magnitude. Addition of SHCs restored meropenem efficacy against 17/19 IMP-type and 7/14 NDM-type MBL-producing Enterobacteriaceae to satisfactory clinical levels. SHCs were also effective against IMP-type MBL-producing Acinetobacter spp. and engineered Escherichia coli strains overproducing individual minor MBLs (i.e., TMB-2, SPM-1, DIM-1, SIM-1, and KHM-1). However, SHCs were less effective against MBL-producing Pseudomonas aeruginosa Combination therapy with meropenem and SHCs successfully cured mice infected with IMP-1-producing E. coli and dually NDM-1/VIM-1-producing Klebsiella pneumoniae clinical isolates. X-ray crystallographic analyses revealed the inhibition mode of SHCs against MBLs; the sulfamoyl group of SHCs coordinated to two zinc ions, and the carboxylate group coordinated to one zinc ion and bound to positively charged amino acids Lys224/Arg228 conserved in MBLs. Preclinical testing revealed that the SHCs showed low toxicity in cell lines and mice and high stability in human liver microsomes. Our results indicate that SHCs are promising lead compounds for inhibitors of MBLs to combat MBL-producing CRE.IMPORTANCE Carbapenem antibiotics are the last resort for control of severe infectious diseases, bloodstream infections, and pneumonia caused by Gram-negative bacteria, including Enterobacteriaceae However, carbapenem-resistant Enterobacteriaceae (CRE) strains have spread globally and are a critical concern in clinical settings because CRE infections are recognized as a leading cause of increased mortality among hospitalized patients. Most CRE produce certain kinds of serine carbapenemases (e.g., KPC- and GES-type β-lactamases) or metallo-β-lactamases (MBLs), which can hydrolyze carbapenems. Although effective MBL inhibitors are expected to restore carbapenem efficacy against MBL-producing CRE, no MBL inhibitor is currently clinically available. Here, we synthesized 2,5-diethyl-1-methyl-4-sulfamoylpyrrole-3-carboxylic acid (SPC), which is a potent inhibitor of MBLs. SPC is a remarkable lead compound for clinically useful MBL inhibitors and can potentially provide a considerable benefit to patients receiving treatment for lethal infectious diseases caused by MBL-producing CRE.

Dataset Information

Carbapenem resistance in Elizabethkingia meningoseptica is mediated by metallo-?-lactamase BlaB.

Publications

Carbapenem resistance in Elizabethkingia meningoseptica is mediated by metallo-β-lactamase BlaB.

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