RNAseq transcriptome analysis of K. pneumoniae MS6671 with PBT2 and colistin
The emergence of polymyxin resistance in carbapenem-resistant and extended-spectrum ?-lactamase (ESBL)-producing bacteria is a critical threat to human health, and new treatment strategies are urgently required. Here, we investigated the ability of the safe-for-human use ionophore PBT2 to restore antibiotic sensitivity in polymyxin-resistant, ESBL-producing, carbapenem-resistant Gram-negative human pathogens. PBT2 was observed to resensitize Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii and Pseudomonas aeruginosa to last-resort polymyxin class antibiotics, including the less-toxic next-generation polymyxin derivative, FADDI-287. We were unable to select for mutants resistant to PBT2 + FADDI-287 in polymyxin resistant E. coli containing a plasmid-borne mcr-1 gene or K. pneumoniae carrying a chromosomal mgrB mutation. Using a highly invasive K. pneumoniae strain engineered for polymyxin resistance through mgrB mutation, we successfully demonstrated the efficacy of PBT2 + FADDI-287 in vivo for the treatment of Gram-negative sepsis. These data present a new treatment modality to break antibiotic resistance in high priority polymyxin-resistant Gram-negative pathogens. Overall design: For K. pneumoniae MS6671, 4 sample conditions were analyzed. Sample conditions included: 1) bacterial treatment with cation-adjusted Muller Hinton broth (CA-MHB; reference sample);  2)  CA-MHB+PBT2 (64 µM); 3) Colistin (0.25 µg/mL); 4) PBT2 + colistin