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

The β-lactam antibiotic ceftazidime is one of only a handful of drugs with proven clinical efficacy against the important opportunistic human pathogen Stenotrophomonas maltophilia. Here, we show that mutations in the energy transducer TonB, encoded by smlt0009 in S. maltophilia, confer ceftazidime resistance and that smlt0009 mutants have reduced uptake of ceftazidime. This breaks the dogma that β-lactams enter Gram-negative bacteria only by passive diffusion through outer membrane porins. We also show that ceftazidime-resistant TonB mutants are cross-resistant to fluoroquinolone antimicrobials and a siderophore-conjugated lactivicin antibiotic designed to target TonB-dependent uptake. This implies that attempts to improve penetration of antimicrobials into S. maltophilia by conjugating them with TonB substrates will suffer from the fact that β-lactams and fluoroquinolones co-select resistance to these novel and otherwise promising antimicrobials. Finally, we show that smlt0009 mutants already exist amongst S. maltophilia clinical isolates, and have reduced susceptibility to siderophore-conjugated lactivicin, despite the in vitro growth impairment seen in smlt0009 mutants selected in the laboratory.