Discovery of ANT3310, a Novel Broad-Spectrum Serine ß-Lactamase Inhibitor of the Diazabicyclooctane Class, Which Strongly Potentiates Meropenem Activity against Carbapenem-Resistant Enterobacterales and Acinetobacter baumannii.

The diazabicyclooctanes (DBOs) are a class of serine ß-lactamase (SBL) inhibitors that use a strained urea moiety as the warhead to react with the active serine residue in the active site of SBLs. The first in-class drug, avibactam, as well as several other recently approved DBOs (e.g., relebactam) or those in clinical development (e.g., nacubactam and zidebactam) potentiate activity of ß-lactam antibiotics, to various extents, against carbapenem-resistant Enterobacterales (CRE) carrying class A, C, and D SBLs; however, none of these are able to rescue the activity of ß-lactam antibiotics against carbapenem-resistant Acinetobacter baumannii (CRAB), a WHO "critical priority pathogen" producing class D OXA-type SBLs. Herein, we describe the chemical optimization and resulting structure-activity relationship, leading to the discovery of a novel DBO, ANT3310, which uniquely has a fluorine atom replacing the carboxamide and stands apart from the current DBOs in restoring carbapenem activity against OXA-CRAB as well as SBL-carrying CRE pathogens.

Re-evaluating the use of beached bird oiling rates to assess long-term trends in chronic oil pollution.

The oiling rate (oiled birds/total birds) has become the international standard to analyze beached bird survey data. However, this index may not reliably track long-term changes in marine oil pollution in regions where other activities that kill seabirds vulnerable to oil, such as hunting and gill-netting, are also changing. We compare the oiling rate from beached bird surveys conducted in southeastern Newfoundland between 1984 and 2006 to an alternative approach, namely trends derived from a model examining the linear density of oiled birds (birds/km). In winter, there was no change in the oiling rate since 1984, while in summer oiling rates significantly increased. In contrast, the number of oiled birds/km showed a significant decline in both winter and summer. The discrepancy in these trends was attributed to steep declines in the number of unoiled birds found in both seasons. In winter, the decline in unoiled birds/km was related to a reduction in the legal murre hunt and less onshore winds, while in summer a reduced cod fishery resulting in fewer murres drowning in nets and warming summers may have lead to the decline. The significant declines in oiled birds/km over the past three decades are hopefully an indication of less oil being present in the marine environment. Although oiled bird densities since 2000 have remained relatively low for the region (winter: 0.58 birds/km, summer: 0.27 birds/km), they still exceed densities reported elsewhere in the world.