Targeting Multidrug-Resistant Acinetobacter spp.: Sulbactam and the Diazabicyclooctenone β-Lactamase Inhibitor ETX2514 as a Novel Therapeutic Agent release_vjh4ly3xjzdsvmgrzv7qb62pfi

Abstract

<jats:title>ABSTRACT</jats:title> Multidrug-resistant (MDR) <jats:italic>Acinetobacter</jats:italic> spp. poses a significant therapeutic challenge in part due to the presence of chromosomally encoded β-lactamases, including class C <jats:italic>Acinetobacter</jats:italic>-derived cephalosporinases (ADC) and class D oxacillinases (OXA), as well as plasmid-mediated class A β-lactamases. Importantly, OXA-like β-lactamases represent a gap in the spectrum of inhibition by recently approved β-lactamase inhibitors such as avibactam and vaborbactam. ETX2514 is a novel, rationally designed, diazabicyclooctenone inhibitor that effectively targets class A, C, and D β-lactamases. We show that addition of ETX2514 significantly increased the susceptibility of clinical <jats:named-content content-type="genus-species">Acinetobacter</jats:named-content><jats:named-content content-type="genus-species"> baumannii</jats:named-content> isolates to sulbactam. AdeB and AdeJ were identified to be key efflux constituents for ETX2514 in <jats:named-content content-type="genus-species">A. baumannii</jats:named-content>. The combination of sulbactam and ETX2514 was efficacious against <jats:named-content content-type="genus-species">A. baumannii</jats:named-content> carrying <jats:italic>bla</jats:italic><jats:sub>TEM-1</jats:sub>, <jats:italic>bla</jats:italic><jats:sub>ADC-82</jats:sub>, <jats:italic>bla</jats:italic><jats:sub>OXA-23</jats:sub>, and <jats:italic>bla</jats:italic><jats:sub>OXA-66</jats:sub> in a neutropenic murine thigh infection model. We also show that, <jats:italic>in vitro</jats:italic>, ETX2514 inhibited ADC-7 (<jats:italic>k</jats:italic><jats:sub>2</jats:sub>/<jats:italic>K<jats:sub>i</jats:sub></jats:italic> 1.0 ± 0.1 × 10<jats:sup>6</jats:sup> M<jats:sup>−1</jats:sup> s<jats:sup>−1</jats:sup>) and OXA-58 (<jats:italic>k</jats:italic><jats:sub>2</jats:sub>/<jats:italic>K<jats:sub>i</jats:sub></jats:italic> 2.5 ± 0.3 × 10<jats:sup>5</jats:sup> M<jats:sup>−1</jats:sup> s<jats:sup>−1</jats:sup>). 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 β-lactamases as well as class A and C β-lactamases and is a promising therapeutic candidate for infections caused by MDR <jats:italic>Acinetobacter</jats:italic> spp. <jats:bold>IMPORTANCE</jats:bold> The number and diversity of β-lactamases are steadily increasing. The emergence of β-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 β-lactamase inhibitors with class D activity. The sulbactam-ETX2514 combination demonstrates the potential to become a treatment regimen of choice for <jats:italic>Acinetobacter</jats:italic> spp. producing class D β-lactamases.
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