Azithromycin Synergizes with Cationic Antimicrobial Peptides to Exert Bactericidal and Therapeutic Activity Against Highly Multidrug-Resistant Gram-Negative Bacterial Pathogens.
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.
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
Leo
L
Lin
Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
Poochit
P
Nonejuie
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
Jason
J
Munguia
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
Andrew
A
Hollands
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
Joshua
J
Olson
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
Quang
Q
Dam
Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Monika
M
Kumaraswamy
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla CA 92093, USA.
Heriberto
H
Rivera
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
Ross
R
Corriden
Central Facility for Microscopy, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.
Manfred
M
Rohde
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
Mary E
ME
Hensler
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla CA 92093, USA.
Michael D
MD
Burkart
Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
Joe
J
Pogliano
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
George
G
Sakoulas
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA ; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA ; Rady Children's Hospital, San Diego, CA 92123, USA.
Victor
V
Nizet
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology* / Q000627:therapeutic use; D017963:Azithromycin / Q000494:pharmacology* / Q000627:therapeutic use; D054804:Cathelicidins / Q000494:pharmacology / Q000627:therapeutic use; D002463:Cell Membrane Permeability / Q000187:drug effects; D003091:Colistin / Q000494:pharmacology / Q000627:therapeutic use; D003470:Culture Media; D004195:Disease Models, Animal; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects*; D004357:Drug Synergism; D005260:Female; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000648:ultrastructure; D006801:Humans; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D003470:Culture Media; D017963:Azithromycin; D003091:Colistin
Acinetobacter baumannii; Antibiotic resistance; Antimicrobial peptides; Azithromycin; Cathelicidin; Colistin; Klebsiella pneumoniae; LL-37; Macrolides; Pseudomonas aeruginosa