Antimicrobial activity of the novel polymyxin derivative NAB739 tested against Gram-negative pathogens

Objectives: In spite of reported nephrotoxicity, polymyxins have been reinstated as the last-line therapy to treat infections caused by Gram-negative bacterial strains that are resistant to other agents. NAB739 has a cyclic portion identical to that of polymyxin B, but its linear peptide portion consists of threonyl-D-serinyl instead of diaminobutyryl-threonyl-diaminobutyryl. Therefore, NAB739 lacks both of the positive charges present in the linear part of polymyxin B. Here, we compare the antibacterial activity of NAB739 with that of polymyxin B against a representative collection of contemporary Gram-negative bacteria. Methods: NAB739 and polymyxin B MIC values were determined for 310 clinical isolates by the reference broth microdilution method according to CLSI document M07-A9 (2012). Results: MIC90s of NAB739 for the subset consisting of polymyxin-susceptible (MIC, ≤2 mg/L) clinical isolates of Escherichia coli (n51), Klebsiella pneumoniae (n50), Acinetobacter spp. (n49) and Pseudomonas aeruginosa (n49) were 2, 2, 8 and 16 mg/L, respectively. For polymyxin-non-susceptible strains of E. coli (n12), K. pneu-moniae (n11), Acinetobacter spp. (n11) and P. aeruginosa (n14) the NAB739 MIC90 was ≥64 mg/L. Conclusions: The MIC90 of NAB739 for polymyxin-susceptible strains of E. coli and K. pneumoniaewas identical to and 2-fold higher than that of polymyxin B, respectively. For polymyxin-susceptible strains of Acinetobacter spp. and P. aeruginosa, the MIC90 of NAB739 was 4-fold and 8-fold higher than that of polymyxin B, respectively. Fo