Azithromycin Synergizes with Cationic Antimicrobial Peptides to Exert Bactericidal and Therapeutic Activity Against Highly Multidrug-Resistant Gram-Negative Bacterial Pathogens

EBioMedicine. 2015 Jun 10;2(7):690-8. doi: 10.1016/j.ebiom.2015.05.021. eCollection 2015 Jul.


Antibiotic resistance poses an increasingly grave threat to the public health. Of pressing concern, rapid spread of carbapenem-resistance among multidrug-resistant (MDR) Gram-negative rods (GNR) is associated with few treatment options and high mortality rates. Current antibiotic susceptibility testing guiding patient management is performed in a standardized manner, identifying minimum inhibitory concentrations (MIC) in bacteriologic media, but ignoring host immune factors. Lacking activity in standard MIC testing, azithromycin (AZM), the most commonly prescribed antibiotic in the U.S., is never recommended for MDR GNR infection. Here we report a potent bactericidal action of AZM against MDR carbapenem-resistant isolates of Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii. This pharmaceutical activity is associated with enhanced AZM cell penetration in eukaryotic tissue culture media and striking multi-log-fold synergies with host cathelicidin antimicrobial peptide LL-37 or the last line antibiotic colistin. Finally, AZM monotherapy exerts clear therapeutic effects in murine models of MDR GNR infection. Our results suggest that AZM, currently ignored as a treatment option, could benefit patients with MDR GNR infections, especially in combination with colistin.

Keywords: Acinetobacter baumannii; Antibiotic resistance; Antimicrobial peptides; Azithromycin; Cathelicidin; Colistin; Klebsiella pneumoniae; LL-37; Macrolides; Pseudomonas aeruginosa.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology*
  • Antimicrobial Cationic Peptides / pharmacology*
  • Antimicrobial Cationic Peptides / therapeutic use
  • Azithromycin / pharmacology*
  • Azithromycin / therapeutic use
  • Cathelicidins / pharmacology
  • Cathelicidins / therapeutic use
  • Cell Membrane Permeability / drug effects
  • Colistin / pharmacology
  • Colistin / therapeutic use
  • Culture Media
  • Disease Models, Animal
  • Drug Resistance, Multiple, Bacterial / drug effects*
  • Drug Synergism
  • Female
  • Gram-Negative Bacteria / drug effects*
  • Gram-Negative Bacteria / ultrastructure
  • Humans
  • Mice, Inbred C57BL
  • Microbial Sensitivity Tests


  • Anti-Bacterial Agents
  • Antimicrobial Cationic Peptides
  • Cathelicidins
  • Culture Media
  • Azithromycin
  • Colistin