title: Antimicrobial activity of the novel polymyxin derivative NAB739 tested against Gram-negative pathogens.
abstract: OBJECTIVE
  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
  MIC(90)s of NAB739 for the subset consisting of polymyxin-susceptible (MIC, ≤ 2 mg/L) clinical isolates of Escherichia coli (n=51), Klebsiella pneumoniae (n=50), Acinetobacter spp. (n=49) and Pseudomonas aeruginosa (n=49) were 2, 2, 8 and 16 mg/L, respectively. For polymyxin-non-susceptible strains of E. coli (n=12), K. pneumoniae (n=11), Acinetobacter spp. (n=11) and P. aeruginosa (n=14) the NAB739 MIC(90) was ≥ 64 mg/L.
  
  
  CONCLUSIONS
  The MIC(90) of NAB739 for polymyxin-susceptible strains of E. coli and K. pneumoniae was identical to and 2-fold higher than that of polymyxin B, respectively. For polymyxin-susceptible strains of Acinetobacter spp. and P. aeruginosa, the MIC(90) of NAB739 was 4-fold and 8-fold higher than that of polymyxin B, respectively. For polymyxin-non-susceptible strains of all these species, the MIC(90) values of NAB739 were high and 2- to 4-fold higher than those of polymyxin B.
authors.affiliation: Northern Antibiotics Ltd, FI-00720 Helsinki, Finland. martti.vaara@northernantibiotics.com
authors.forename: Martti
authors.initials: M
authors.lastname: Vaara
authors.forename: Helio S
authors.initials: HS
authors.lastname: Sader
authors.forename: Paul R
authors.initials: PR
authors.lastname: Rhomberg
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Jones
authors.forename: Timo
authors.initials: T
authors.lastname: Vaara
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000302:isolation & purification; D016905:Gram-Negative Bacterial Infections / Q000382:microbiology; D006801:Humans; D008826:Microbial Sensitivity Tests; D011113:Polymyxins / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; C546019:NAB 739 peptide; D011113:Polymyxins