A microbiological and structural analysis of the interplay between sulbactam/durlobactam and imipenem against penicillin-binding proteins (PBPs) of <i>Acinetobacter</i> spp.

In the ATTACK Phase 3 trial examining the efficacy of sulbactam (SUL)/durlobactam (DUR) to treat primarily <i>Acinetobacter baumannii</i> complex (ABC) infections, imipenem (IPM)/cilastatin was added as a common therapy to both the SUL/DUR and the comparator colistin arms. This raised the question of whether the use of IPM in the SUL/DUR arm of the study influenced the efficacy of SUL/DUR. To investigate this issue on a microbiological and molecular level, we performed static concentration time-kill studies and molecular modeling of binding of SUL to PBP1a and PBP3, IPM to PBP1a, PBP2, and PBP3, and DUR to OXA-23 and OXA-51. The time-kill studies performed using carbapenemase- and non-carbapenemase-producing isolates demonstrated synergy between SUL and IPM in the presence of DUR, supporting the notion that the efficacy of the SUL/DUR arm against <i>Acinetobacter</i> spp. in the ATTACK trial was enhanced by the addition of IPM. We also hypothesize that the protection of SUL and IPM from OXA carbapenemases by DUR enabled IPM and SUL to synergistically deactivate multiple PBPs ("target redundancy"). Docking simulations supported the favorable binding of SUL to PBP1a and PBP3, resulting in the formation of acyl-enzyme complexes. Molecular docking analysis of OXA carbapenemase enzymes with DUR also revealed favorable interactions. Although clinical trials are warranted, these analyses provide mechanistic support for the addition of IPM to SUL/DUR.