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

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          Abstract

          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.

          Highlights

          • Standard MIC testing conditions overlook a potent activity of azithromycin vs. multidrug-resistant Gram-negative bacteria.

          • Colistin and endogenous host defense peptide LL-37 markedly potentiate azithromycin penetration into bacterial cells.

          • Azithromycin reduced bacterial load and mortality in mouse models of multidrug-resistant Gram-negative infection.

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          Most cited references43

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          The biology and future prospects of antivirulence therapies.

          The emergence and increasing prevalence of bacterial strains that are resistant to available antibiotics demand the discovery of new therapeutic approaches. Targeting bacterial virulence is an alternative approach to antimicrobial therapy that offers promising opportunities to inhibit pathogenesis and its consequences without placing immediate life-or-death pressure on the target bacterium. Certain virulence factors have been shown to be potential targets for drug design and therapeutic intervention, whereas new insights are crucial for exploiting others. Targeting virulence represents a new paradigm to empower the clinician to prevent and treat infectious diseases.
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            Modulating immunity as a therapy for bacterial infections.

            Despite our efforts to halt the increase and spread of antimicrobial resistance, bacteria continue to become less susceptible to antimicrobial drugs over time, and rates of discovery for new antibiotics are declining. Thus, it is essential to explore new paradigms for anti-infective therapy. One promising approach involves host-directed immunomodulatory therapies, whereby natural mechanisms in the host are exploited to enhance therapeutic benefit. The objective is to initiate or enhance protective antimicrobial immunity while limiting inflammation-induced tissue injury. A range of potential immune modulators have been proposed, including innate defence regulator peptides and agonists of innate immune components such as Toll-like receptors and NOD-like receptors.
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              Fluorometric assessment of gram-negative bacterial permeabilization.

              Uptake of the fluorescent probe 1-N-phenylnaphthylamine (NPN), as adapted to an automated spectrofluorometer enabling multiwell reading of microtitre plates, was applied to determine permeability changes in Gram-negative bacteria. An intact outer membrane is a permeability barrier, and excludes hydrophobic substances such as NPN but, once damaged, it can allow the entry of NPN to the phospholipid layer, resulting in prominent fluorescence. With Escherichia coli O157, Pseudomonas aeruginosa, and Salmonella typhimurium as test organisms and ethylenediaminetetraacetic acid and sodium hexametaphosphate as the model permeabilizers, quantitative and highly reproducible NPN uptake levels were obtained that differed characteristically between the test bacteria. Furthermore, citric acid was shown to be a potent permeabilizer at millimolar concentrations, its effect being partly (Ps. aeruginosa, Salm. typhimurium) or almost totally (E. coli O157) abolished by MgCl2, suggesting that part of the action occurs by chelation. Sodium citrate induced weak NPN uptake, which was totally abolished by MgCl2. In conclusion, the NPN uptake assay with the automated spectrofluorometer serves as a convenient method in analysing and quantifying the effects of external agents, including potential food preservatives, on Gram-negative bacteria.
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                Author and article information

                Contributors
                Journal
                EBioMedicine
                EBioMedicine
                EBioMedicine
                Elsevier
                2352-3964
                10 June 2015
                July 2015
                10 June 2015
                : 2
                : 7
                : 690-698
                Affiliations
                [a ]Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA
                [b ]Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA
                [c ]Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
                [d ]Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla CA 92093, USA
                [e ]Central Facility for Microscopy, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany
                [f ]Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA
                [g ]Rady Children's Hospital, San Diego, CA 92123, USA
                Author notes
                [* ]Corresponding author. l2lin@ 123456ucsd.edu
                [** ]Correspondence to: V. Nizet, Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA. vnizet@ 123456ucsd.edu
                [1]

                These authors contributed equally.

                Article
                S2352-3964(15)30024-4
                10.1016/j.ebiom.2015.05.021
                4534682
                26288841
                49057c62-9de5-4fd3-a634-b8c621a98945
                © 2015 The Authors. Published by Elsevier B.V.

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 18 May 2015
                : 21 May 2015
                : 21 May 2015
                Categories
                Original Article

                azithromycin,macrolides,antimicrobial peptides,cathelicidin,ll-37,antibiotic resistance,colistin,pseudomonas aeruginosa,acinetobacter baumannii,klebsiella pneumoniae

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