The key features of this unusual, dual BLI combination therapy are described below.
#Pbp3 class b plus#
The only agent currently in late-stage clinical development for this indication is a combination of sulbactam, a first generation β-lactamase inhibitor (BLI) with intrinsic antibacterial activity against Acinetobacter spp., plus durlobactam, a next generation diazabicyclooctane (DBO) β-lactamase inhibitor with broad-spectrum activity against Class A, C, and D β-lactamases ( Durand-Reville et al., 2017). These findings have recently been proposed to be related to liabilities associated with siderophore-mediated uptake leading to heteroresistance ( Choby et al., 2021).
#Pbp3 class b trial#
baumannii bloodstream infections or nosocomial pneumonia in the recent CREDIBLE-CR Phase 3 trial ( Bassetti et al., 2021). In addition, treatment with this agent resulted in higher mortality rates as compared to best available therapy in patients with A. Although cefiderocol (Fetroja ®), which was recently approved for the treatment of drug-resistant Gram-negative pathogens, has potent in vitro activity against MDR Acinetobacter ( Isler et al., 2019), its in vivo efficacy in preclinical infection models of infection against cefiderocol-susceptible Acinetobacter baumannii is quite variable ( Monogue et al., 2017).
![pbp3 class b pbp3 class b](https://www.researchgate.net/publication/289602044/figure/fig2/AS:560874802298880@1510734381534/Overall-structure-of-PBP3-and-electron-density-maps-A-Rainbow-coloured-cartoon.png)
In the past few decades, resistance to carbapenems in Acinetobacter and even the last resort agent colistin, has also increased at alarming rates worldwide ( Lee et al., 2017).ĭespite the significant unmet medical need, there are currently no reliably effective antibiotics for the treatment of carbapenem-resistant Acinetobacter infections. Clinical resistance in this organism to nearly all antibiotic classes, including cephalosporins, fluoroquinolones, aminoglycosides, and tetracyclines, is widespread and continues to increase ( Magiorakos et al., 2012 Wong et al., 2017). The incidence of these infections varies widely across the globe, ranging from 1% of surgical site infections and 12% of VAP in the United States ( Weiner et al., 2016) to 35% of all hospital-acquired drug-resistant infections in China ( Zhang et al., 2019). Most Acinetobacter infections are chronic, with mortality rates of 40–60% ( Wong et al., 2017).
#Pbp3 class b skin#
These pathogens cause hospital-acquired or ventilator-associated pneumonia (VAP), bacteremia, complicated urinary tract infections and a variety of skin and tissue infections, in both healthy and immuno-compromised individuals ( Lee et al., 2017). Infections caused by multi-drug resistant (MDR) Acinetobacter species are among the most urgent threats to human health.
![pbp3 class b pbp3 class b](https://www.researchgate.net/profile/Andrew-Tomaras/publication/49661726/figure/fig2/AS:667768999383053@1536219944913/Overall-structure-of-the-high-molecular-weight-class-B-PBP3-from-Gram-negative-bacteria_Q640.jpg)
#Pbp3 class b drivers#
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. 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.
![pbp3 class b pbp3 class b](https://s1.cdn.autoevolution.com/images/news/gallery/production-ready-mercedes-benz-b-class-electric-drive-videophoto-gallery_5.jpg)
However, when combined with durlobactam, the activity of sulbactam is effectively restored against these notoriously multidrug-resistant strains. Because sulbactam is also susceptible to cleavage by numerous β-lactamases, its clinical utility for the treatment of contemporary Acinetobacter infections is quite limited. 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. 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.