Xeruborbactam (formerly QPX7728) is a cyclic boronate inhibitor of numerous serine and metallo-beta-lactamases. At concentrations generally higher than those required for beta-lactamase inhibition, xeruborbactam has direct antibacterial activity against some Gram-negative bacteria, with MIC/MIC values of 16/32 μg/mL and 16/64 μg/mL against carbapenem-resistant and carbapenem-resistant Acinetobacter baumannii, respectively (the MIC/MIC values against Pseudomonas aeruginosa are >64 μg/mL). In Klebsiella pneumoniae, inactivation of OmpK36 alone or in combination with OmpK35 resulted in 2- to 4-fold increases in the xeruborbactam MIC. In A. baumannii and P. aeruginosa, AdeIJK and MexAB-OprM, respectively, affected xeruborbactam's antibacterial potency (the MICs were 4- to 16-fold higher in efflux-proficient strains). In Escherichia coli and K. pneumoniae, the 50% inhibitory concentrations (ICs) of xeruborbactam's binding to penicillin-binding proteins (PBPs) PBP1a/PBP1b, PBP2, and PBP3 were in the 40 to 70 μM range; in A. baumannii, xeruborbactam bound to PBP1a, PBP2, and PBP3 with ICs of 1.4 μM, 23 μM, and 140 μM, respectively. Treating K. pneumoniae and P. aeruginosa with xeruborbactam at 1× and 2× MIC resulted in changes of cellular morphology similar to those observed with meropenem; the morphological changes observed after treatment of A. baumannii were consistent with inhibition of multiple PBPs but were unique to xeruborbactam compared to the results for control beta-lactams. No single-step xeruborbactam resistance mutants were obtained after selection at 4× MIC of xeruborbactam using wild-type strains of E. coli, K. pneumoniae, and A. baumannii; mutations selected at 2× MIC in K. pneumoniae did not affect antibiotic potentiation by xeruborbactam through beta-lactamase inhibition. Consistent with inhibition of PBPs, xeruborbactam enhanced the potencies of beta-lactam antibiotics even against strains that lacked beta-lactamase. In a large panel of KPC-producing clinical isolates, the MIC values of meropenem tested with xeruborbactam (8 μg/mL) were at least 4-fold lower than those in combination with vaborbactam at 64 μg/mL, the concentration of vaborbactam that is associated with complete inhibition of KPC. The additional enhancement of the potency of beta-lactam antibiotics beyond beta-lactamase inhibition may contribute to the potentiation of beta-lactam antibiotics by xeruborbactam.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9578396 | PMC |
http://dx.doi.org/10.1128/aac.00879-22 | DOI Listing |
Antimicrob Agents Chemother
January 2025
Microbiology department, A Coruna University Hospital (CHUAC), Institute of Biomedical Research of A Coruna (INIBIC), A Coruna, Spain.
Carbapenemase OXA-48 and its variants pose a serious threat to the development of effective treatments for bacterial infections. OXA-48-producing Enterobacterales are the most prevalent carbapenemase-producing bacteria in large parts of the world. Although these bacteria exhibit low-level carbapenem resistance , the infections they cause are challenging to treat with conventional therapies, owing to their spread and complex detection in clinical settings.
View Article and Find Full Text PDFChem Commun (Camb)
November 2024
Department of Biomolecular Systems, Max-Planck-Institute of Colloids and Interfaces, 14476 Potsdam, Germany.
Bicyclic boronates have recently emerged as promising candidates to invoke targeted biomolecular interactions, given their selectivity for specific functionalities. Despite this, the general stability of the C-B bond , for such heterocycles, remains an intractable challenge that can often preclude their utility in drug discovery. To address this challenge, strategies that allow expedient access to strategically substituted boronates, that enable modulation of the C-B bond are urgently required.
View Article and Find Full Text PDFAntimicrob Agents Chemother
November 2024
Servicio de Microbiología Clínica e Instituto de Investigación Biomédica A Coruña (INIBIC), Complexo Hospitalario Universitario A Coruña, A Coruña, Spain.
Expert Rev Anti Infect Ther
December 2024
Departments of Laboratory Medicine and Internal Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan.
Antimicrob Agents Chemother
November 2024
Medical and Molecular Microbiology, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland.
The relative inhibitory activities of diazabicyclooctanes (avibactam, relebactam, zidebactam, nacubactam, durlobactam), boronic acid derivatives (vaborbactam, taniborbactam, xeruborbactam), and penicillin-based sulfone derivative enmetazobactam were evaluated against several intrinsic and acquired class C β-lactamases. By contrast to vaborbactam and enmetazobactam, taniborbactam, xeruborbactam, and all diazabicyclooctanes demonstrated effective activities against most AmpC enzymes. Notably, durlobactam exhibited the most pronounced inhibitory effect.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!