ETX2514 is a broad-spectrum β-lactamase inhibitor for the treatment of drug-resistant Gram-negative bacteria including Acinetobacter baumannii

Durand-Réville, Thomas F.; Guler, Satenig; Comita-Prevoir, Janelle; Chen, Brendan; Bifulco, Neil; Huynh, Hoan K.; Lahiri, S. C.; Shapiro, Adam B.; McLeod, Sarah M.; Carter, Nicole; Moussa, Samir H.; Velez-Vega, Camilo; Olivier, N.B.; McLaughlin, Robert E.; Gao, Ning; Thresher, Jason; Palmer, Tiffany; Andrews, Beth; Giacobbe, Robert A.; Newman, Joseph V.; Ehmann, David E.; Jonge, Boudewijn de; O’Donnell, John P.; Mueller, John P.; Tommasi, Rubén; Miller, Alita A.

doi:10.1038/nmicrobiol.2017.104

Cited by 209 publications

(302 citation statements)

References 39 publications

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“…[292,301] Four DBO-based compounds are currently in development and differ from avibactam by substitution at the amide at position 2( Figure 21). [308] Ab oronate-based compound, VNRX-5133 from Vena-toRx is in clinical phase I. [302,303] Zidebactam, a3 -piperidinylcarbonyl hydrazide from Wockhardt is in phase Ii nc ombination with cefepime and targets class Aand C b-lactamases.Remarkably for aBLI, the compound also inhibits PBP2 of Gram-negative pathogens and thereby shows antibacterial properties against some Enterobacteriaceae and P. aeruginosa.…”

Section: B-lactamase Inhibitors (Blis)mentioning

confidence: 99%

Thinking Outside the Box—Novel Antibacterials To Tackle the Resistance Crisis

et al. 2018

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The public view on antibiotics as reliable medicines changed when reports about "resistant superbugs" appeared in the news. While reasons for this resistance development are easily spotted, solutions for re-establishing effective antibiotics are still in their infancy. This Review encompasses several aspects of the antibiotic development pipeline from very early strategies to mature drugs. An interdisciplinary overview is given of methods suitable for mining novel antibiotics and strategies discussed to unravel their modes of action. Select examples of antibiotics recently identified by using these platforms not only illustrate the efficiency of these measures, but also highlight promising clinical candidates with therapeutic potential. Furthermore, the concept of molecules that disarm pathogens by addressing gatekeepers of virulence will be covered. The Review concludes with an evaluation of antibacterials currently in clinical development. Overall, this Review aims to connect select innovative antimicrobial approaches to stimulate interdisciplinary partnerships between chemists from academia and industry.

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Section: B-lactamase Inhibitors (Blis)mentioning

confidence: 99%

Thinking Outside the Box—Novel Antibacterials To Tackle the Resistance Crisis

et al. 2018

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“…Preclinical studies show potent in vitro and in vivo activity with sulbactam-durlobactam against A. baumannii (12–14). Phase 1 clinical studies in healthy subjects have characterized the pharmacokinetic (PK) profile of durlobactam after single and multiple ascending doses and in combination with sulbactam and determined plasma and intrapulmonary concentrations of both components (15, 16).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics, Safety, and Tolerability of Intravenous Durlobactam and Sulbactam in Subjects with Renal Impairment and Healthy Matched Control Subjects

O’Donnell

Preston

Mamikonyan³

et al. 2019

Antimicrob Agents Chemother

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Sulbactam-durlobactam is being developed for the treatment of infections caused by Acinetobacter baumannii, including those caused by multidrug- and carbapenem-resistant isolates. This was a phase 1 study to evaluate the effects of various degrees of renal impairment, including subjects with end-stage renal disease (ESRD) on hemodialysis (HD), on the pharmacokinetics and safety profile of durlobactam (also known as ETX2514) and sulbactam after single intravenous (i.v.) dose administration. For healthy subjects and those with mild or moderate renal impairment (RI), single 1,000-mg doses each of durlobactam and sulbactam via a 3-h i.v. infusion were administered, and for severe renal impairment, 500-mg doses were administered. For subjects with ESRD and HD, 500-mg i.v. doses each of durlobactam and sulbactam were administered post-HD and pre-HD, with a 1-week washout between doses. Among 34 subjects, decreasing renal function increased systemic exposure (peak plasma concentration [Cmax] and area under the concentration-time curve [AUC]) to durlobactam and sulbactam in a generally linear manner. In healthy subjects and in those with mild or moderate renal impairment, the majority of durlobactam and sulbactam was excreted in the urine, while approximately 40% or less was excreted in urine in subjects with severe renal impairment or ESRD. In subjects with ESRD, hemodialysis was effective at removing both durlobactam and sulbactam from plasma. Renal impairment had no effect of the safety/tolerability profile of durlobactam and sulbactam. In summary, RI and ESRD had a predictable effect on the pharmacokinetic (PK) profile of durlobactam and sulbactam with no adverse effects on the safety/tolerability profile. Durlobactam and sulbactam are cleared to a similar extent by renal elimination and are impacted similarly by renal impairment. The results from this study have been used with population PK modeling and nonclinically derived PK/PD (pharmacodynamic) exposure targets to establish dosage recommendations for durlobactam and sulbactam in patients with various degrees of RI. The dosing regimen of durlobactam-sulbactam will require adjustment in patients with severe renal insufficiency and in those with ESRD.

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“…Besides the above‐mentioned enzymes, some notorious bacterial enzymes, like β‐lactamases, were also used to specially eradicate the multidrug‐resistant pathogenic bacteria and selectively preserve the probiotics . Different from other methods of inhibiting or removing β‐lactamase, this β‐lactamase‐responsive drug release system provided a powerful alternative to combat the multidrug‐resistant bacteria. Generally, proteases are seldom used in triggering drug release, mainly limited by their poor selectivity.…”

Section: Adaptive Antimicrobial‐delivery Systemsmentioning

confidence: 99%

Recent Advances and Future Prospects on Adaptive Biomaterials for Antimicrobial Applications

Liu

et al. 2019

Macromolecular Bioscience

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Bacterial infection is becoming the biggest threat to human health. The scenario is partly due to the ineffectiveness of the conventional antibiotic treatments against the emergence of multidrug‐resistant bacteria and partly due to the bacteria living in biofilms or cells. Adaptive biomaterials can change their physicochemical properties in the microenvironment of bacterial infection, thereby facilitating either their interactions with bacteria or drug release. The trends in treating bacterial infections using adaptive biomaterials‐based systems are flourishing and generate innumerous possibility to design novel antimicrobial therapeutics. This feature article aims to summarize the recent developments in the formulations, mechanisms, and advances of adaptive materials in bacterial infection diagnosis, contact killing of bacteria, and antimicrobial drug delivery. Also, the challenges and limitations of current antimicrobial treatments based on adaptive materials and their clinical and industrial future prospects are discussed.

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ETX2514 is a broad-spectrum β-lactamase inhibitor for the treatment of drug-resistant Gram-negative bacteria including Acinetobacter baumannii

Cited by 209 publications

References 39 publications

Thinking Outside the Box—Novel Antibacterials To Tackle the Resistance Crisis

Thinking Outside the Box—Novel Antibacterials To Tackle the Resistance Crisis

Pharmacokinetics, Safety, and Tolerability of Intravenous Durlobactam and Sulbactam in Subjects with Renal Impairment and Healthy Matched Control Subjects

Recent Advances and Future Prospects on Adaptive Biomaterials for Antimicrobial Applications

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