title: Antimicrobial Peptide Novicidin Synergizes with Rifampin, Ceftriaxone, and Ceftazidime against Antibiotic-Resistant Enterobacteriaceae In Vitro.
abstract: The spread of antibiotic resistance among Gram-negative bacteria is a serious clinical threat, and infections with these organisms are a leading cause of mortality worldwide. Traditional novel drug development inevitably leads to the emergence of new resistant strains, rendering the new drugs ineffective. Therefore, reviving the therapeutic potentials of existing antibiotics represents an attractive novel strategy. Novicidin, a novel cationic antimicrobial peptide, is effective against Gram-negative bacteria. Here, we investigated novicidin as a possible antibiotic enhancer. The actions of novicidin in combination with rifampin, ceftriaxone, or ceftazidime were investigated against 94 antibiotic-resistant clinical Gram-negative isolates and 7 strains expressing New Delhi metallo-β-lactamase-1. Using the checkerboard method, novicidin combined with rifampin showed synergy with >70% of the strains, reducing the MICs significantly. The combination of novicidin with ceftriaxone or ceftazidime was synergistic against 89.7% of the ceftriaxone-resistant strains and 94.1% of the ceftazidime-resistant strains. Synergistic interactions were confirmed using time-kill studies with multiple strains. Furthermore, novicidin increased the postantibiotic effect when combined with rifampin or ceftriaxone. Membrane depolarization assays revealed that novicidin alters the cytoplasmic membrane potential of Gram-negative bacteria. In vitro toxicology tests showed novicidin to have low hemolytic activity and no detrimental effect on cell cultures. We demonstrated that novicidin strongly rejuvenates the therapeutic potencies of ceftriaxone or ceftazidime against resistant Gram-negative bacteria in vitro. In addition, novicidin boosted the activity of rifampin. This strategy can have major clinical implications in our fight against antibiotic-resistant bacterial infections.
authors.affiliation: Institute for Infection and Immunity, St George's, University of London, London, United Kingdom.
authors.forename: Odel
authors.initials: O
authors.lastname: Soren
authors.affiliation: Novozymes A/S, Bagsvaerd, Denmark.
authors.forename: Karoline Sidelmann
authors.initials: KS
authors.lastname: Brinch
authors.affiliation: Institute for Infection and Immunity, St George's, University of London, London, United Kingdom.
authors.forename: Dipesh
authors.initials: D
authors.lastname: Patel
authors.affiliation: Institute for Infection and Immunity, St George's, University of London, London, United Kingdom.
authors.forename: Yingjun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
authors.forename: Alexander
authors.initials: A
authors.lastname: Liu
authors.affiliation: Institute for Infection and Immunity, St George's, University of London, London, United Kingdom.
authors.forename: Anthony
authors.initials: A
authors.lastname: Coates
authors.affiliation: Institute for Infection and Immunity, St George's, University of London, London, United Kingdom ymhu@sgul.ac.uk.
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Hu
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D002442:Ceftazidime / Q000494:pharmacology*; D002443:Ceftriaxone / Q000494:pharmacology*; D002460:Cell Line; D004352:Drug Resistance, Microbial / Q000187:drug effects*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004754:Enterobacter / Q000187:drug effects / Q000254:growth & development; D004912:Erythrocytes / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development; D005347:Fibroblasts / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000254:growth & development; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008826:Microbial Sensitivity Tests; D012293:Rifampin / Q000494:pharmacology*; D012705:Serratia / Q000187:drug effects / Q000254:growth & development
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; C554278:novicidin; D002443:Ceftriaxone; D002442:Ceftazidime; D012293:Rifampin