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1.
BMC Microbiol ; 19(1): 150, 2019 07 04.
Article in English | MEDLINE | ID: mdl-31272373

ABSTRACT

BACKGROUND: The prevalence of antibiotic resistance is increasing, and multidrug-resistant Pseudomonas aeruginosa has been identified as a serious threat to human health. The production of ß-lactamase is a key mechanism contributing to imipenem resistance in P. aeruginosa. Relebactam is a novel ß-lactamase inhibitor, active against class A and C ß-lactamases, that has been shown to restore imipenem susceptibility. In a series of studies, we assessed the interaction of relebactam with key mechanisms involved in carbapenem resistance in P. aeruginosa and to what extent relebactam might overcome imipenem non-susceptibility. RESULTS: Relebactam demonstrated no intrinsic antibacterial activity against P. aeruginosa, had no inoculum effect, and was not subject to efflux. Enzymology studies showed relebactam is a potent (overall inhibition constant: 27 nM), practically irreversible inhibitor of P. aeruginosa AmpC. Among P. aeruginosa clinical isolates from the SMART global surveillance program (2009, n = 993; 2011, n = 1702; 2015, n = 5953; 2016, n = 6165), imipenem susceptibility rates were 68.4% in 2009, 67.4% in 2011, 70.4% in 2015, and 67.3% in 2016. With the addition of 4 µg/mL relebactam, imipenem susceptibility rates increased to 87.6, 86.0, 91.7, and 89.8%, respectively. When all imipenem-non-susceptible isolates were pooled, the addition of 4 µg/mL relebactam reduced the mode imipenem minimum inhibitory concentration (MIC) 8-fold (from 16 µg/mL to 2 µg/mL) among all imipenem-non-susceptible isolates. Of 3747 imipenem-non-susceptible isolates that underwent molecular profiling, 1200 (32%) remained non-susceptible to the combination imipenem/relebactam (IMI/REL); 42% of these encoded class B metallo-ß-lactamases, 11% encoded a class A GES enzyme, and no class D enzymes were detected. No relationship was observed between alleles of the chromosomally-encoded P. aeruginosa AmpC and IMI/REL MIC. CONCLUSIONS: IMI/REL exhibited potential in the treatment of carbapenem-resistant P. aeruginosa infections, with the exception of isolates encoding class B, some GES alleles, and class D carbapenemases.


Subject(s)
Azabicyclo Compounds/pharmacology , Imipenem/pharmacology , Pseudomonas aeruginosa/drug effects , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/drug effects , Drug Combinations , Drug Resistance, Multiple, Bacterial/drug effects , Humans , Kinetics , Microbial Sensitivity Tests , Pseudomonas Infections/microbiology , Pseudomonas aeruginosa/enzymology , beta-Lactamases/drug effects
2.
Chem Biol ; 22(10): 1362-73, 2015 Oct 22.
Article in English | MEDLINE | ID: mdl-26456734

ABSTRACT

Resistance to existing classes of antibiotics drives the need for discovery of novel compounds with unique mechanisms of action. Nargenicin A1, a natural product with limited antibacterial spectrum, was rediscovered in a whole-cell antisense assay. Macromolecular labeling in both Staphylococcus aureus and an Escherichia coli tolC efflux mutant revealed selective inhibition of DNA replication not due to gyrase or topoisomerase IV inhibition. S. aureus nargenicin-resistant mutants were selected at a frequency of ∼1 × 10(-9), and whole-genome resequencing found a single base-pair change in the dnaE gene, a homolog of the E. coli holoenzyme α subunit. A DnaE single-enzyme assay was exquisitely sensitive to inhibition by nargenicin, and other in vitro characterization studies corroborated DnaE as the target. Medicinal chemistry efforts may expand the spectrum of this novel mechanism antibiotic.


Subject(s)
DNA Polymerase III/genetics , Drug Discovery , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/metabolism , Anti-Bacterial Agents/pharmacology , DNA Replication/drug effects , DNA-Directed DNA Polymerase/metabolism , Drug Resistance, Bacterial/genetics , Escherichia coli/drug effects , Inhibitory Concentration 50 , Lactones/chemistry , Lactones/metabolism , Lactones/pharmacology , Mutation , Nucleic Acid Synthesis Inhibitors/chemistry , Nucleic Acid Synthesis Inhibitors/pharmacology , Staphylococcus aureus/drug effects
3.
Antimicrob Agents Chemother ; 59(2): 1052-60, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25451052

ABSTRACT

Clostridium difficile infections (CDIs) are the leading cause of hospital-acquired infectious diarrhea and primarily involve two exotoxins, TcdA and TcdB. Actoxumab and bezlotoxumab are human monoclonal antibodies that neutralize the cytotoxic/cytopathic effects of TcdA and TcdB, respectively. In a phase II clinical study, the actoxumab-bezlotoxumab combination reduced the rate of CDI recurrence in patients who were also treated with standard-of-care antibiotics. However, it is not known whether the antibody combination will be effective against a broad range of C. difficile strains. As a first step toward addressing this, we tested the ability of actoxumab and bezlotoxumab to neutralize the activities of toxins from a number of clinically relevant and geographically diverse strains of C. difficile. Neutralization potencies, as measured in a cell growth/survival assay with purified toxins from various C. difficile strains, correlated well with antibody/toxin binding affinities. Actoxumab and bezlotoxumab neutralized toxins from culture supernatants of all clinical isolates tested, including multiple isolates of the BI/NAP1/027 and BK/NAP7/078 strains, at antibody concentrations well below plasma levels observed in humans. We compared the bezlotoxumab epitopes in the TcdB receptor binding domain across known TcdB sequences and found that key substitutions within the bezlotoxumab epitopes correlated with the relative differences in potencies of bezlotoxumab against TcdB of some strains, including ribotypes 027 and 078. Combined with in vitro neutralization data, epitope modeling will enhance our ability to predict the coverage of new and emerging strains by actoxumab-bezlotoxumab in the clinic.


Subject(s)
Anti-Bacterial Agents/pharmacology , Antibodies, Monoclonal/pharmacology , Clostridioides difficile/drug effects , Bacterial Proteins/genetics , Cell Line , Clostridioides difficile/immunology , Clostridioides difficile/pathogenicity , Clostridium Infections/drug therapy , Clostridium Infections/microbiology , Epitopes/immunology , Female , Humans , Male
4.
Bioorg Med Chem Lett ; 24(3): 780-5, 2014 Feb 01.
Article in English | MEDLINE | ID: mdl-24433862

ABSTRACT

ß-Lactamase inhibitors with a bicyclic urea core and a variety of heterocyclic side chains were prepared and evaluated as potential partners for combination with imipenem to overcome class A and C ß-lactamase mediated antibiotic resistance. The piperidine analog 3 (MK-7655) inhibited both class A and C ß-lactamases in vitro. It effectively restored imipenem's activity against imipenem-resistant Pseudomonas and Klebsiella strains at clinically achievable concentrations. A combination of MK-7655 and Primaxin® is currently in phase II clinical trials for the treatment of Gram-negative bacterial infections.


Subject(s)
Azabicyclo Compounds/chemistry , Azabicyclo Compounds/pharmacology , Cilastatin/chemistry , Drug Discovery , Enzyme Inhibitors/chemistry , Imipenem/chemistry , beta-Lactamase Inhibitors , Cilastatin/pharmacology , Cilastatin, Imipenem Drug Combination , Crystallography, X-Ray , Drug Combinations , Drug Resistance, Bacterial/drug effects , Imipenem/pharmacology , Inhibitory Concentration 50 , Klebsiella/drug effects , Microbial Sensitivity Tests , Models, Biological , Pseudomonas/drug effects , Structure-Activity Relationship
5.
Bioorg Med Chem Lett ; 21(14): 4267-70, 2011 Jul 15.
Article in English | MEDLINE | ID: mdl-21676616

ABSTRACT

The bridged monobactam ß-lactamase inhibitor MK-8712 (1) effectively inhibits class C ß-lactamases. Side chain N-alkylated and ring-opened analogs of 1 were prepared and evaluated for combination with imipenem to overcome class C ß-lactamase mediated resistance. Although some analogs were more potent inhibitors of AmpC, none exhibited better synergy with imipenem than 1.


Subject(s)
Anti-Bacterial Agents/chemistry , Enzyme Inhibitors/chemistry , Monobactams/chemical synthesis , beta-Lactamase Inhibitors , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Binding Sites , Computer Simulation , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Imipenem/pharmacology , Microbial Sensitivity Tests , Monobactams/pharmacology , Protein Structure, Tertiary , Structure-Activity Relationship , beta-Lactamases/metabolism
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