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Bulgecin A as a β -lactam enhancer for carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Acinetobacter baumannii clinical isolates containing various resistance mechanisms

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ABSTRACT

Genetic screening of Pseudomonas aeruginosa (PSDA) and Acinetobacter baumannii (ACB) reveals genes that confer increased susceptibility to β-lactams when disrupted, suggesting novel drug targets. One such target is lytic transglycosylase. Bulgecin A (BlgA) is a natural product of Pseudomonas mesoacidophila and a lytic transglycosolase inhibitor that works synergistically with β-lactams targeting PBP3 for Enterobacteriaceae. BlgA also weakly inhibits di-Zn2+ metallo-β-lactamases like L1 of Stenotrophomonas maltophilia. We hypothesized that because of its unique mechanism of action, BlgA could restore susceptibility to carbapenems in carbapenem-resistant PSDA (CR-PSDA) and carbapenem-resistant ACB, as well as ACB resistant to sulbactam. A BlgA-containing extract was prepared using a previously published protocol. CR-PSDA clinical isolates demonstrating a variety of carbapenem resistance mechanisms (VIM-2 carbapenemases, efflux mechanisms, and AmpC producer expression) were characterized with agar dilution minimum inhibitory concentration (MIC) testing and polymerase chain reaction. Growth curves using these strains were prepared using meropenem, BlgA extract, and meropenem plus BlgA extract. A concentrated Blg A extract combined with low concentrations of meropenem, was able to inhibit the growth of clinical strains of CR-PSDA for strains that had meropenem MICs ≥8 mg/L by agar dilution, and a clinical strain of an OXA-24 producing ACB that had a meropenem MIC >32 mg/L and intermediate ampicillin/sulbactam susceptibility. Similar experiments were conducted on a TEM-1 producing ACB strain resistant to sulbactam. BlgA with ampicillin/sulbactam inhibited the growth of this organism. As in Enterobacteriaceae, BlgA appears to restore the efficacy of meropenem in suppressing the growth of CR-PSDA and carbapenem-resistant ACB strains with a variety of common carbapenem resistance mechanisms. BlgA extract also inhibits VIM-2 β-lactamase in vitro. BlgA may prove to be an exciting adjunctive compound to extend the life of carbapenems against these vexing pathogens.

No MeSH data available.


Bulgecin A.
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f1-dddt-10-3013: Bulgecin A.

Mentions: BlgA (Figure 1) is an inhibitor of the soluble Escherichia coli Ltg, Slt70,21 and has been found to dramatically lower the minimum inhibitory concentrations (MICs) of ampicillin and cefmenoxime when combined with these agents and tested against E. coli and Helicobacter pylori strains.16,22 BlgA is a natural product derived from Pseudomonas mesoacidophila, a nonpathogenic strain that also produces monobactam antibiotics.22–24 The name derives from the bulge-like morphologic changes observed in Enterobacteriaceae when such organisms are grown in the presence of β-lactams and BlgA.22,25 Structurally, it contains a GlcNAC moiety like the substrate of Ltgs, and thus acts as a transition state inhibitor of Ltgs.26 BlgA appears to exert its effect when combined with β-lactams that target PBP3 in Enterobacteriaceae as a noncompetitive inhibitor of Ltgs.17,21 X-ray structures of Slt70 of E. coli demonstrate that the hydroxymethyl side chain of the pyrrolidine ring hydrogen bonds to the catalytic Glu478 in the manner of a transition state analog of the GlcNAC–MurNAC substrate.13,21


Bulgecin A as a β -lactam enhancer for carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Acinetobacter baumannii clinical isolates containing various resistance mechanisms
Bulgecin A.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5036594&req=5

f1-dddt-10-3013: Bulgecin A.
Mentions: BlgA (Figure 1) is an inhibitor of the soluble Escherichia coli Ltg, Slt70,21 and has been found to dramatically lower the minimum inhibitory concentrations (MICs) of ampicillin and cefmenoxime when combined with these agents and tested against E. coli and Helicobacter pylori strains.16,22 BlgA is a natural product derived from Pseudomonas mesoacidophila, a nonpathogenic strain that also produces monobactam antibiotics.22–24 The name derives from the bulge-like morphologic changes observed in Enterobacteriaceae when such organisms are grown in the presence of β-lactams and BlgA.22,25 Structurally, it contains a GlcNAC moiety like the substrate of Ltgs, and thus acts as a transition state inhibitor of Ltgs.26 BlgA appears to exert its effect when combined with β-lactams that target PBP3 in Enterobacteriaceae as a noncompetitive inhibitor of Ltgs.17,21 X-ray structures of Slt70 of E. coli demonstrate that the hydroxymethyl side chain of the pyrrolidine ring hydrogen bonds to the catalytic Glu478 in the manner of a transition state analog of the GlcNAC–MurNAC substrate.13,21

View Article: PubMed Central - PubMed

ABSTRACT

Genetic screening of Pseudomonas aeruginosa (PSDA) and Acinetobacter baumannii (ACB) reveals genes that confer increased susceptibility to β-lactams when disrupted, suggesting novel drug targets. One such target is lytic transglycosylase. Bulgecin A (BlgA) is a natural product of Pseudomonas mesoacidophila and a lytic transglycosolase inhibitor that works synergistically with β-lactams targeting PBP3 for Enterobacteriaceae. BlgA also weakly inhibits di-Zn2+ metallo-β-lactamases like L1 of Stenotrophomonas maltophilia. We hypothesized that because of its unique mechanism of action, BlgA could restore susceptibility to carbapenems in carbapenem-resistant PSDA (CR-PSDA) and carbapenem-resistant ACB, as well as ACB resistant to sulbactam. A BlgA-containing extract was prepared using a previously published protocol. CR-PSDA clinical isolates demonstrating a variety of carbapenem resistance mechanisms (VIM-2 carbapenemases, efflux mechanisms, and AmpC producer expression) were characterized with agar dilution minimum inhibitory concentration (MIC) testing and polymerase chain reaction. Growth curves using these strains were prepared using meropenem, BlgA extract, and meropenem plus BlgA extract. A concentrated Blg A extract combined with low concentrations of meropenem, was able to inhibit the growth of clinical strains of CR-PSDA for strains that had meropenem MICs ≥8 mg/L by agar dilution, and a clinical strain of an OXA-24 producing ACB that had a meropenem MIC >32 mg/L and intermediate ampicillin/sulbactam susceptibility. Similar experiments were conducted on a TEM-1 producing ACB strain resistant to sulbactam. BlgA with ampicillin/sulbactam inhibited the growth of this organism. As in Enterobacteriaceae, BlgA appears to restore the efficacy of meropenem in suppressing the growth of CR-PSDA and carbapenem-resistant ACB strains with a variety of common carbapenem resistance mechanisms. BlgA extract also inhibits VIM-2 β-lactamase in vitro. BlgA may prove to be an exciting adjunctive compound to extend the life of carbapenems against these vexing pathogens.

No MeSH data available.