Azithromycin Synergizes with Cationic Antimicrobial Peptides to Exert Bactericidal and Therapeutic Activity Against Highly Multidrug-Resistant Gram-Negative Bacterial Pathogens
Leo Lin,
Poochit Nonejuie,
Jason Munguia,
Andrew Hollands,
Joshua Olson,
Quang Dam,
Monika Kumaraswamy,
Heriberto Rivera Jr.,
Ross Corriden,
Manfred Rohde,
Mary E. Hensler,
Michael D. Burkart,
Joe Pogliano,
George Sakoulas,
Victor Nizet
Affiliations
Leo Lin
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA
Poochit Nonejuie
Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA
Jason Munguia
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA
Andrew Hollands
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA
Joshua Olson
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA
Quang Dam
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA
Monika Kumaraswamy
Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
Heriberto Rivera Jr.
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla CA 92093, USA
Ross Corriden
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA
Manfred Rohde
Central Facility for Microscopy, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany
Mary E. Hensler
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA
Michael D. Burkart
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla CA 92093, USA
Joe Pogliano
Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA
George Sakoulas
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA
Victor Nizet
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA
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.
