Dataset Information

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.

Project description:Metallo-β-lactamases (MBLs) represent one of the main causes of carbapenem resistance in the order Enterobacterales. To combat MBL-producing carbapenem-resistant Enterobacterales, the development of MBL inhibitors can restore carbapenem efficacy for such resistant bacteria. Microbial natural products are a promising source of attractive seed compounds for the development of antimicrobial agents. Here, we report that hydroxyhexylitaconic acids (HHIAs) produced by a member of the genus Aspergillus can suppress carbapenem resistance conferred by MBLs, particularly IMP (imipenemase)-type MBLs. HHIAs were found to be competitive inhibitors with micromolar orders of magnitude against IMP-1 and showed weak inhibitory activity toward VIM-2, while no inhibitory activity against NDM-1 was observed despite the high dosage. The elongated methylene chains of HHIAs seem to play a crucial role in exerting inhibitory activity because itaconic acid, a structural analog without long methylene chains, did not show inhibitory activity against IMP-1. The addition of HHIAs restored meropenem and imipenem efficacy to satisfactory clinical levels against IMP-type MBL-producing Escherichia coli and Klebsiella pneumoniae clinical isolates. Unlike EDTA and Aspergillomarasmine A, HHIAs did not cause the loss of zinc ions from the active site, resulting in the structural instability of MBLs. X-ray crystallography and in silico docking simulation analyses revealed that two neighboring carboxylates of HHIAs coordinated with two zinc ions in the active sites of VIM-2 and IMP-1, which formed a key interaction observed in MBL inhibitors. Our results indicated that HHIAs are promising for initiating the design of potent inhibitors of IMP-type MBLs.IMPORTANCEThe number and type of metallo-β-lactamase (MΒL) are increasing over time. Carbapenem resistance conferred by MΒL is a significant threat to our antibiotic regimen, and the development of MΒL inhibitors is urgently required to restore carbapenem efficacy. Microbial natural products have served as important sources for developing antimicrobial agents targeting pathogenic bacteria since the discovery of antibiotics in the mid-20th century. MΒL inhibitors derived from microbial natural products are still rare compared to those derived from chemical compound libraries. Hydroxyhexylitaconic acids (HHIAs) produced by members of the genus Aspergillus have potent inhibitory activity against clinically relevant IMP-type MBL. HHIAs may be good lead compounds for the development of MBL inhibitors applicable for controlling carbapenem resistance in IMP-type MBL-producing Enterobacterales.

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.

Similar Datasets

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