Avibactam Restores the Susceptibility of Clinical Isolates of Stenotrophomonas maltophilia to Aztreonam

Abstract

Stenotrophomonas maltophilia is an emerging opportunistic pathogen, classified by the World Health Organization as one of the leading multidrug-resistant organisms in hospital settings. The need to discover novel compounds and/or combination therapies for S. maltophilia is urgent. We demonstrate the in vitro efficacy of aztreonam-avibactam (ATM-AVI) against S. maltophilia and kinetically characterize the inhibition of the L2 β-lactamase by avibactam. ATM-AVI overcomes aztreonam resistance in selected clinical strains of S. maltophilia, addressing an unmet medical need.

Keywords: S. maltophilia; avibactam; aztreonam.

FIG 1

Avibactam is a potent inhibitor of L2. (A and B) ESI-MS spectrum of unreacted L2 (170 nM) (A) and 1:1 molar ratio of L2 and AVI (170 nM) (B) incubated at room temperature in 10 mM phosphate-buffered saline (PBS) (pH 7.4) for 15 s. Spectra obtained after 1-min, 15-min, 1-h, and 24-h incubations of L2 and AVI were identical to those in panel B. (C) Molecular docking of L2 and AVI. The L2 crystal structure (PDB no. 1N4O) is represented as a gray ribbon; AVI is displayed as sticks colored by heteroatoms (pink, carbon; red, oxygen; blue, nitrogen; yellow, sulfur). (D) Interactions of AVI with L2. Interacting residues are displayed in gray, while AVI is represented by pink. Heteroatoms are colored as described before. Interacting waters are shown in blue with their corresponding hydrogen bonds displayed as blue dashed lines; distances between important atoms are highlighted by yellow arrows; hydrogen bonds between residues are indicated by green dashed lines.