Dataset Information

Frequency and Mechanism of Spontaneous Resistance to Sulbactam Combined with the Novel ?-Lactamase Inhibitor ETX2514 in Clinical Isolates of Acinetobacter baumannii.

ABSTRACT: The novel diazabicyclooctenone ETX2514 is a potent, broad-spectrum serine ?-lactamase inhibitor that restores sulbactam activity against resistant Acinetobacter baumannii The frequency of spontaneous resistance to sulbactam-ETX2514 in clinical isolates was found to be 7.6 × 10-10 to <9.0 × 10-10 at 4× MIC and mapped to residues near the active site of penicillin binding protein 3 (PBP3). Purified mutant PBP3 proteins demonstrated reduced affinity for sulbactam. In a sulbactam-sensitive isolate, resistance also mapped to stringent response genes associated with resistance to PBP2 inhibitors, suggesting that in addition to ?-lactamase inhibition, ETX2514 may enhance sulbactam activity in A. baumannii via inhibition of PBP2.

SUBMITTER: McLeod SM

PROVIDER: S-EPMC5786785 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Publications

Frequency and Mechanism of Spontaneous Resistance to Sulbactam Combined with the Novel β-Lactamase Inhibitor ETX2514 in Clinical Isolates of Acinetobacter baumannii.

McLeod Sarah M SM Shapiro Adam B AB Moussa Samir H SH Johnstone Michele M McLaughlin Robert E RE de Jonge Boudewijn L M BLM Miller Alita A AA

Antimicrobial agents and chemotherapy 20180125 2

The novel diazabicyclooctenone ETX2514 is a potent, broad-spectrum serine β-lactamase inhibitor that restores sulbactam activity against resistant Acinetobacter baumannii The frequency of spontaneous resistance to sulbactam-ETX2514 in clinical isolates was found to be 7.6 × 10-10 to <9.0 × 10-10 at 4× MIC and mapped to residues near the active site of penicillin binding protein 3 (PBP3). Purified mutant PBP3 proteins demonstrated reduced affinity for sulbactam. In a ...[more]

PMID: 29133555

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Project description:Multidrug-resistant (MDR) Acinetobacter spp. poses a significant therapeutic challenge in part due to the presence of chromosomally encoded ?-lactamases, including class C Acinetobacter-derived cephalosporinases (ADC) and class D oxacillinases (OXA), as well as plasmid-mediated class A ?-lactamases. Importantly, OXA-like ?-lactamases represent a gap in the spectrum of inhibition by recently approved ?-lactamase inhibitors such as avibactam and vaborbactam. ETX2514 is a novel, rationally designed, diazabicyclooctenone inhibitor that effectively targets class A, C, and D ?-lactamases. We show that addition of ETX2514 significantly increased the susceptibility of clinical Acinetobacter baumannii isolates to sulbactam. AdeB and AdeJ were identified to be key efflux constituents for ETX2514 in A. baumannii The combination of sulbactam and ETX2514 was efficacious against A. baumannii carrying bla TEM-1, bla ADC-82, bla OXA-23, and bla OXA-66 in a neutropenic murine thigh infection model. We also show that, in vitro, ETX2514 inhibited ADC-7 (k 2/Ki 1.0?±?0.1?×?106 M-1 s-1) and OXA-58 (k 2/Ki 2.5?±?0.3?×?105 M-1 s-1). Cocrystallization of ETX2514 with OXA-24/40 revealed hydrogen bonding interactions between ETX2514 and residues R261, S219, and S128 of OXA-24/40 in addition to a chloride ion occupied in the active site. Further, the C3 methyl group of ETX2514 shifts the position of M223. In conclusion, the sulbactam-ETX2514 combination possesses a broadened inhibitory range to include class D ?-lactamases as well as class A and C ?-lactamases and is a promising therapeutic candidate for infections caused by MDR Acinetobacter spp.IMPORTANCE The number and diversity of ?-lactamases are steadily increasing. The emergence of ?-lactamases that hydrolyze carbapenems poses a significant threat to our antibiotic armamentarium. The explosion of OXA enzymes that are carbapenem hydrolyzers is a major challenge (carbapenem-hydrolyzing class D [CHD]). An urgent need exists to discover ?-lactamase inhibitors with class D activity. The sulbactam-ETX2514 combination demonstrates the potential to become a treatment regimen of choice for Acinetobacter spp. producing class D ?-lactamases.

Dataset Information

Frequency and Mechanism of Spontaneous Resistance to Sulbactam Combined with the Novel ?-Lactamase Inhibitor ETX2514 in Clinical Isolates of Acinetobacter baumannii.

Publications

Frequency and Mechanism of Spontaneous Resistance to Sulbactam Combined with the Novel β-Lactamase Inhibitor ETX2514 in Clinical Isolates of Acinetobacter baumannii.

Similar Datasets

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