Dataset Information

Durlobactam, a New Diazabicyclooctane β-Lactamase Inhibitor for the Treatment of Acinetobacter Infections in Combination With Sulbactam.

ABSTRACT: Durlobactam is a new member of the diazabicyclooctane class of β-lactamase inhibitors with broad spectrum activity against Ambler class A, C, and D serine β-lactamases. Sulbactam is a first generation β-lactamase inhibitor with activity limited to a subset of class A enzymes that also has direct-acting antibacterial activity against Acinetobacter spp. The latter feature is due to sulbactam's ability to inhibit certain penicillin-binding proteins, essential enzymes involved in bacterial cell wall synthesis in this pathogen. Because sulbactam is also susceptible to cleavage by numerous β-lactamases, its clinical utility for the treatment of contemporary Acinetobacter infections is quite limited. However, when combined with durlobactam, the activity of sulbactam is effectively restored against these notoriously multidrug-resistant strains. This sulbactam-durlobactam combination is currently in late-stage development for the treatment of Acinectobacter infections, including those caused by carbapenem-resistant isolates, for which there is a high unmet medical need. The following mini-review summarizes the molecular drivers of efficacy of this combination against this troublesome pathogen, with an emphasis on the biochemical features of each partner.

SUBMITTER: Shapiro AB

PROVIDER: S-EPMC8328114 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

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.

Project description:ObjectivesCefepime/taniborbactam is a cephalosporin/cyclic boronate β-lactamase inhibitor combination under development for the treatment of infections due to MDR Enterobacterales and Pseudomonas aeruginosa. Using a neutropenic murine thigh infection model, we aimed to determine the pharmacokinetic/pharmacodynamic index, relative to taniborbactam exposure, that correlated most closely with the efficacy of the cefepime/taniborbactam combination and the magnitude of index required for efficacy against serine-β-lactamase-producing strains.MethodsTwenty-six clinical Enterobacterales (expressing ESBLs, plasmid-mediated AmpC and/or carbapenemases of classes A or D; cefepime/taniborbactam combination MICs 0.06-16 mg/L) and 11 clinical P. aeruginosa (AmpC overproducing or KPC expressing; cefepime/taniborbactam combination MICs 1-16 mg/L) were evaluated. A cefepime human-simulated regimen (HSR) equivalent to a clinical dose of 2 g q8h as a 2 h infusion was given in combination with taniborbactam for 24 h. For a subset of P. aeruginosa isolates, a sub-therapeutic cefepime exposure was utilized.ResultsDose-fractionation studies revealed that dosing frequency had no impact on taniborbactam potentiation of cefepime activity. Relative to the initial bacterial burden, the median taniborbactam fAUC0-24/MIC associated with 1 log kill in combination with the cefepime HSR for Enterobacterales and P. aeruginosa isolates was 2.62 and 0.46, respectively. In combination with sub-therapeutic cefepime, the median taniborbactam fAUC0-24/MIC associated with 1 and 2 log kill against AmpC-overproducing P. aeruginosa was 2.00 and 3.30, respectively, relative to the bacterial burden in the cefepime-treated groups. The taniborbactam HSR (equivalent to 0.5 g q8h as a 2 h infusion) was adequate to attain ≥1 log reduction against all test isolates.ConclusionsOur data show that the cefepime/taniborbactam combination (2 g/0.5 g q8h as a 2 h infusion) exerts potent in vivo activity against cefepime-resistant isolates, including serine-carbapenemase producers.

Project description:The need to develop beta-lactamase inhibitors against class C cephalosporinases of Gram-negative pathogens represents an urgent clinical priority. To respond to this challenge, five boronic acid derivatives, including a new cefoperazone analogue, were synthesized and tested against the class C cephalosporinase of Acinetobacter baumannii [Acinetobacter-derived cephalosporinase (ADC)]. The commercially available carbapenem antibiotics were also assayed. In the boronic acid series, a chiral cephalothin analogue with a meta-carboxyphenyl moiety corresponding to the C(3)/C(4) carboxylate of beta-lactams showed the lowest K(i) (11 +/- 1 nM). In antimicrobial susceptibility tests, this cephalothin analogue lowered the ceftazidime and cefotaxime minimum inhibitory concentrations (MICs) of Escherichia coli DH10B cells carrying bla(ADC) from 16 to 4 microg/mL and from 8 to 1 microg/mL, respectively. On the other hand, each carbapenem exhibited a K(i) of <20 microM, and timed electrospray ionization mass spectrometry (ESI-MS) demonstrated the formation of adducts corresponding to acyl-enzyme intermediates with both intact carbapenem and carbapenem lacking the C(6) hydroxyethyl group. To improve our understanding of the interactions between the beta-lactamase and the inhibitors, we constructed models of ADC as an acyl-enzyme intermediate with (i) the meta-carboxyphenyl cephalothin analogue and (ii) the carbapenems, imipenem and meropenem. Our first model suggests that this chiral cephalothin analogue adopts a novel conformation in the beta-lactamase active site. Further, the addition of the substituent mimicking the cephalosporin dihydrothiazine ring may significantly improve affinity for the ADC beta-lactamase. In contrast, the ADC-carbapenem models offer a novel role for the R(2) side group and also suggest that elimination of the C(6) hydroxyethyl group by retroaldolic reaction leads to a significant conformational change in the acyl-enzyme intermediate. Lessons from the diverse mechanisms and structures of the boronic acid derivatives and carbapenems provide insights for the development of new beta-lactamase inhibitors against these critical drug resistance targets.

Dataset Information

Durlobactam, a New Diazabicyclooctane β-Lactamase Inhibitor for the Treatment of Acinetobacter Infections in Combination With Sulbactam.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure