Novel β-lactamase inhibitors: a therapeutic hope against the scourge of multidrug resistance.

The increasing incidence and prevalence of multi-drug resistance (MDR) among contemporary Gram-negative bacteria represents a significant threat to human health. Since their discovery, β-lactam antibiotics have been a major component of the armamentarium against these serious pathogens. Unfortunately, a wide range of β-lactamase enzymes have emerged that are capable of inactivating these powerful drugs.

Complete sequence of a KPC-producing IncN multidrug-resistant plasmid from an epidemic Escherichia coli sequence type 131 strain in China.

We report here the nucleotide sequence of a novel blaKPC-2-harboring incompatibility group N (IncN) plasmid, pECN580, from a multidrug-resistant Escherichia coli sequence type 131 (ST131) isolate recovered from Beijing, China. pECN580 harbors β-lactam resistance genes blaKPC-2, blaCTX-M-3, and blaTEM-1; aminoglycoside acetyltransferase gene aac(6')-Ib-cr; quinolone resistance gene qnrS1; rifampin resistance gene arr-3; and trimethoprim resistance gene dfrA14. The emergence of a blaKPC-2-harboring multidrug-resistant plasmid in an epidemic E.

Host-specific enzyme-substrate interactions in SPM-1 metallo-β-lactamase are modulated by second sphere residues.

Pseudomonas aeruginosa is one of the most virulent and resistant non-fermenting Gram-negative pathogens in the clinic. Unfortunately, P. aeruginosa has acquired genes encoding metallo-β-lactamases (MβLs), enzymes able to hydrolyze most β-lactam antibiotics.

New β-lactamase inhibitors: a therapeutic renaissance in an MDR world.

As the incidence of Gram-negative bacterial infections for which few effective treatments remain increases, so does the contribution of drug-hydrolyzing β-lactamase enzymes to this serious clinical problem. This review highlights recent advances in β-lactamase inhibitors and focuses on agents with novel mechanisms of action against a wide range of enzymes. To this end, we review the β-lactamase inhibitors currently in clinical trials, select agents still in preclinical development, and older therapeutic approaches that are being revisited.

A kinetic analysis of the inhibition of FOX-4 β-lactamase, a plasmid-mediated AmpC cephalosporinase, by monocyclic β-lactams and carbapenems.

Objectives: Class C β-lactamases are prevalent among Enterobacteriaceae; however, these enzymes are resistant to inactivation by commercially available β-lactamase inhibitors. In order to find novel scaffolds to inhibit class C β-lactamases, the comparative efficacy of monocyclic β-lactam antibiotics (aztreonam and the siderophore monosulfactam BAL30072), the bridged monobactam β-lactamase inhibitor BAL29880, and carbapenems (imipenem, meropenem, doripenem and ertapenem) were tested in kinetic assays against FOX-4, a plasmid-mediated class C β-lactamase (pmAmpC).

Methods: The FOX-4 β-lactamase was purified.

Better tests, better care: improved diagnostics for infectious diseases.

In this IDSA policy paper, we review the current diagnostic landscape, including unmet needs and emerging technologies, and assess the challenges to the development and clinical integration of improved tests. To fulfill the promise of emerging diagnostics, IDSA presents recommendations that address a host of identified barriers. Achieving these goals will require the engagement and coordination of a number of stakeholders, including Congress, funding and regulatory bodies, public health agencies, the diagnostics industry, healthcare systems, professional societies, and individual clinicians.

β-Lactamase inhibition by 7-alkylidenecephalosporin sulfones: allylic transposition and formation of an unprecedented stabilized acyl-enzyme.

The inhibition of the class A SHV-1 β-lactamase by 7-(tert-butoxycarbonyl)methylidenecephalosporin sulfone was examined kinetically, spectroscopically, and crystallographically. An 1.14 Å X-ray crystal structure shows that the stable acyl-enzyme, which incorporates an eight-membered ring, is a covalent derivative of Ser70 linked to the 7-carboxy group of 2-H-5,8-dihydro-1,1-dioxo-1,5-thiazocine-4,7-dicarboxylic acid.

Draft Genome Sequence of the Clinical Isolate Acinetobacter nosocomialis Strain M2.

We report the 3.78-Mbp high-quality draft assembly of the genome from a clinical isolate of Acinetobacter nosocomialis called strain M2 (previously known as Acinetobacter baumannii strain M2).

Structural origins of oxacillinase specificity in class D β-lactamases.

Since the discovery and use of penicillin, the increase of antibiotic resistance among bacterial pathogens has become a major health concern. The most prevalent resistance mechanism in Gram-negative bacteria is due to β-lactamase expression. Class D β-lactamases are of particular importance due to their presence in multidrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa.

Non-phenotypic tests to detect and characterize antibiotic resistance mechanisms in Enterobacteriaceae.

In the past 2 decades, we have observed a rapid increase of infections due to multidrug-resistant Enterobacteriaceae. Regrettably, these isolates possess genes encoding for extended-spectrum β-lactamases (e.g.

Can inhibitor-resistant substitutions in the Mycobacterium tuberculosis β-Lactamase BlaC lead to clavulanate resistance?: a biochemical rationale for the use of β-lactam-β-lactamase inhibitor combinations.

The current emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis calls for novel treatment strategies. Recently, BlaC, the principal β-lactamase of Mycobacterium tuberculosis, was recognized as a potential therapeutic target. The combination of meropenem and clavulanic acid, which inhibits BlaC, was found to be effective against even extensively drug-resistant M.

Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases.

Klebsiella pneumoniae carbapenemases (KPCs) were originally identified in the USA in 1996. Since then, these versatile β-lactamases have spread internationally among Gram-negative bacteria, especially K pneumoniae, although their precise epidemiology is diverse across countries and regions. The mortality described among patients infected with organisms positive for KPC is high, perhaps as a result of the limited antibiotic options remaining (often colistin, tigecycline, or aminoglycosides).

PCR and electrospray ionization mass spectrometry for detection of persistent enterococcus faecalis in cerebrospinal fluid following treatment of postoperative ventriculitis.

We describe the use of PCR and electrospray ionization followed by mass spectrometry (PCR/ESI-MS) to evaluate "culture-negative" cerebrospinal fluid (CSF) from a 67-year-old man who developed postoperative bacterial ventriculitis following a suboccipital craniotomy for resection of an ependymoma in the 4th ventricle. CSF samples were obtained on seven occasions, beginning in the operating room at the time of insertion of a right ventriculoperitoneal shunt (VPS) and continuing until his death, 6 weeks later. During the course of the illness, two initial CSF specimens taken before the initiation of antimicrobial treatment were notable for growth of Enterococcus faecalis.

Class D β-lactamases: a reappraisal after five decades.

Despite 70 years of clinical use, β-lactam antibiotics still remain at the forefront of antimicrobial chemotherapy. The major challenge to these life-saving therapeutics is the presence of bacterial enzymes (i.e.

Complete nucleotide sequence of a blaKPC-harboring IncI2 plasmid and its dissemination in New Jersey and New York hospitals.

Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae strains have spread worldwide and become a significant public health threat. blaKPC, the plasmid-borne KPC gene, was frequently identified on numerous transferable plasmids in different incompatibility replicon groups.

Structures of the class D Carbapenemases OXA-23 and OXA-146: mechanistic basis of activity against carbapenems, extended-spectrum cephalosporins, and aztreonam.

Class D β-lactamases that hydrolyze carbapenems such as imipenem and doripenem are a recognized danger to the efficacy of these "last-resort" β-lactam antibiotics. Like all known class D carbapenemases, OXA-23 cannot hydrolyze the expanded-spectrum cephalosporin ceftazidime. OXA-146 is an OXA-23 subfamily clinical variant that differs from the parent enzyme by a single alanine (A220) inserted in the loop connecting β-strands β5 and β6.

"Salvage microbiology": detection of bacteria directly from clinical specimens following initiation of antimicrobial treatment.

Background: PCR coupled with electrospray ionization mass spectrometry (ESI-MS) is a diagnostic approach that has demonstrated the capacity to detect pathogenic organisms from culture negative clinical samples after antibiotic treatment has been initiated. [1] We describe the application of PCR/ESI-MS for detection of bacteria in original patient specimens that were obtained after administration of antibiotic treatment in an open investigation analysis.

Methods: We prospectively identified cases of suspected bacterial infection in which cultures were not obtained until after the initiation of antimicrobial treatment.

Insights into β-lactamases from Burkholderia species, two phylogenetically related yet distinct resistance determinants.

Burkholderia cepacia complex and Burkholderia pseudomallei are opportunistic human pathogens. Resistance to β-lactams among Burkholderia spp. is attributable to expression of β-lactamases (e.

Genome Sequences of Two Klebsiella pneumoniae Isolates from Different Geographical Regions, Argentina (Strain JHCK1) and the United States (Strain VA360).

We report the sequences of two Klebsiella pneumoniae clinical isolates, strains JHCK1 and VA360, from a newborn with meningitis in Buenos Aires, Argentina, and from a tertiary care medical center in Cleveland, OH, respectively. Both isolates contain one chromosome and at least five plasmids; isolate VA360 contains the Klebsiella pneumoniae carbapenemase (KPC) gene.

10 x '20 Progress--development of new drugs active against gram-negative bacilli: an update from the Infectious Diseases Society of America.

Infections caused by antibiotic-resistant bacteria, especially the "ESKAPE" pathogens, continue to increase in frequency and cause significant morbidity and mortality. New antimicrobial agents are greatly needed to treat infections caused by gram-negative bacilli (GNB) resistant to currently available agents. The Infectious Diseases Society of America (IDSA) continues to propose legislative, regulatory, and funding solutions to this continuing crisis.