Escherichia coli with penicillin-binding protein 3 insertions: implications for newer β-lactam/β-lactamase inhibitor combinations

ABSTRACT Escherichia coli with penicillin-binding protein 3 (PBP3) insertions appeared in the early 2000s and expanded during the 2010s. The YRIN and YRIK variants predominate globally, while other insertion types remain rare. These insertions frequently co-occur with carbapenemases (NDM-5 and OXA-181) and high-risk clones (ST410, ST167, and ST405), contributing to the evolution and dissemination of multidrug resistance. Newer β-lactam/β-lactamase inhibitor combinations (ceftazidime/avibactam, aztreonam/avibactam, and cefepime/taniborbactam) and cefiderocol with affinities for PBP3 show reduced activity against E. coli with YRIN and YRIK insertions. The continued spread of such strains threatens the effectiveness of these β-lactam agents. In contrast, agents targeting PBP2, such as cefepime/zidebactam and cefiderocol-xeruborbactam, retain potent in vitro activity and will likely be important for future treatment strategies. Laboratory methods to detect PBP3 insertions are lacking, raising concern that these strains may be spreading largely undetected. Current surveillance efforts are insufficient, leaving significant gaps in data describing the global distribution and prevalence of E. coli with PBP3 insertions. The convergence of β-lactamase production and PBP target modification represents a paradigm shift within E. coli toward multidrug resistance. This occurrence provides a major barrier to current and future β-lactam/β-lactamase inhibitor development. There is an urgent need for enhanced global surveillance, along with rapid diagnostic tools capable of identifying PBP3 insertions and associated high-risk clones among carbapenemase-producing E. coli . Future strategies should prioritize agents with activities against multiple essential PBPs to preserve β-lactam efficacy.