Dear All (and with thanks to Robert Bonomo and Patricia Bradford for guiding me on this newsletter; anything that's correct is due to Patricia and Robert; all the mistakes are mine!), This wonkish note has a short, simple version above my signature and then a longer version below by signature. The beta-lactam / beta-lactamase wizards will have to forgive the simplifications! The basic plot for this note is that an emerging form of resistance in Gram-negative bacteria (PBP3 mutations) threatens our limited pool of BL-BLI (beta-lactam — beta-lactamase inhibitor) combinations that are active in the presence of metallo-beta-lactamases (MBLs).  This problem was exemplified most recently in Fabrizio 2026 (and discussed further in Stellfox 2026). These papers discuss a clinical report of infection due to an E. coli strain which was carrying (i) serine-beta-lactamases, (ii) MBLs, (iii) a PBP3 mutation, and (iv) a mutation in the iron uptake system.  Here's the short, simple version:A Gram-negative bacterium can become effectively resistant to (almost) all current BL-BLI combinations by carrying the triad of:Serine beta-lactamasesMetallo beta-lactamasesA mutation in PBP3 (the target of many of the beta-lactams)If you are both lucky and clever (as shown in Fabrizio 2026), it might be possible to design a drug combination that sidesteps...