TonB dependent uptake of β-lactam antibiotics in the opportunistic human pathogen Stenotrophomonas maltophilia

Abstract The β-lactam antibiotic ceftazidime is one of only a handful of drugs with proven clinical efficacy against the opportunistic human pathogen Stenotrophomonas maltophilia, Here, we show that mutations in the energy transducer TonB, encoded by smlt0009 in S. maltophilia, confer ceftazidime resistance. This breaks the dogma that β-lactams enter Gram-negative bacteria only by passive diffusion through outer membrane porins. By confirming cross-resistance of Smlt0009 mutants with a siderophore-conjugated lactivicin antibiotic, we reveal that attempts to improve penetration of antimicrobials into Gram negative bacteria by conjugating them with TonB substrates is likely to select β-lactam resistance in S. maltophilia, increasing its clinical threat. Furthermore, we show that S. maltophilia clinical isolates that have an Smlt0009 mutation already exist. Remarkably, therefore, β-lactam use is already eroding the potential utility of currently experimental siderophore-conjugated antimicrobials against this species.