Predicting tigecycline susceptibility in multidrug-resistant Klebsiella species and Escherichia coli strains of environmental origin

Tigecycline (TGC) is an important antimicrobial agent used as a last resort for difficult-to-treat infections mainly caused by carbapenem-resistant Enterobacteriaceae, but TGC-resistant strains are emerging, raising concerns. In this study, 33 whole-genome characterized multidrug-resistant (MDR) strains (Klebsiella species and Escherichia coli) positive mainly to mcr-1, bla, and/or qnr from the environment were investigated for TGC susceptibility and mutations in TGC resistance determinants, predicting a genotype-phenotype relationship. TGC minimum inhibitory concentrations (MICs) of Klebsiella species and E. coli ranged from 0.25 to 8 and 0.125 to 0.5 mg/L, respectively. In this context, KPC-2-producing Klebsiella pneumoniae ST11 and Klebsiella quasipneumoniae subsp. quasipneumoniae ST4417 strains were resistant to TGC, while some E. coli strains of ST10 clonal complex positive for mcr-1 and/or bla(CTX-M) exhibited reduced susceptibility to this antimicrobial. Overall, neutral and deleterious mutations were shared among TGC-susceptible and TGC-resistant strains. A new frameshift mutation (Q16stop) in RamR was found in a K. quasipneumoniae strain and was associated with TGC resistance. Deleterious mutations in OqxR were identified in Klebsiella species and appear to be associated with decreased susceptibility to TGC. All E. coli strains were determined as susceptible, but multiple point mutations were identified, highlighting deleterious mutations in ErmY, WaaQ, EptB, and RfaE in strains exhibiting decreased susceptibility to TGC. These findings demonstrate that resistance to TGC is not widespread in environmental MDR strains and provide genomic insights about resistance and decreased susceptibility to TGC. From a One Health perspective, the monitoring of TGC susceptibility should be constant, improving the genotype-phenotype relationship and genetic basis.