Membrane Interactions of Novicidin, a Novel Antimicrobial Peptide: Phosphatidylglycerol Promotes Bilayer Insertion

Dorosz, Jerzy; Gofman, Yana; Kolusheva, Sofiya; Otzen, Daniel E.; Ben‐Tal, Nir; Nielsen, Niels Chr.; Jelinek, Raz

doi:10.1021/jp1052248

Cited by 24 publications

(24 citation statements)

References 58 publications

(104 reference statements)

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“…This subsequently causes membrane perturbation and transient pore formation and is bactericidal via the resulting leakage of bacterial cell contents (13)(14)(15). Significant antimicrobial effects have been noted with several Gram-negative organisms, such as Escherichia coli and Salmonella enterica (15).…”

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confidence: 99%

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Antimicrobial Peptide Novicidin Synergizes with Rifampin, Ceftriaxone, and Ceftazidime against Antibiotic-Resistant Enterobacteriaceae In Vitro

Soren

Brinch

Patel

et al. 2015

Antimicrob Agents Chemother

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cThe 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-␤-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.

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confidence: 99%

“…Novicidin was developed from ovispirin, which in turn originated from an ovine cathelicidin known as sheep myeloid antimicrobial peptide 29 (SMAP-29) (13). This allowed for the construction of a peptide more suitable for use as a therapeutic agent (14).…”

mentioning

confidence: 99%

Antimicrobial Peptide Novicidin Synergizes with Rifampin, Ceftriaxone, and Ceftazidime against Antibiotic-Resistant Enterobacteriaceae In Vitro

Soren

Brinch

Patel

et al. 2015

Antimicrob Agents Chemother

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“…Novicidin (KNLRRIIRKGIHIIKKYF), a synthetic peptide derived from the ovine cathelicidin SMAP-29 (30), was generously provided by Dr. Hans-Henrik Kristensen (Novozymes, Copenhagen, Denmark).…”

Section: Methodsmentioning

confidence: 99%

“…3, A and B). BSA has a 2-3 orders of magnitude lower binding affinity for the GA module compared with HSA and was therefore included as an irrelevant control (30). Pretreatment of bacteria (strain G45wt) with BSA did not increase the survival on cytokine-activated epithelial cells.…”

Section: Killing Of Ggs By Mig/cxcl9 Is Blocked By Hsa-mig/mentioning

confidence: 99%

Binding of Albumin Promotes Bacterial Survival at the Epithelial Surface

Egesten

Frick

Mörgelin

et al. 2011

Journal of Biological Chemistry

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Human serum albumin (HSA) is the dominating protein in human plasma. Many bacterial species, especially streptococci, express surface proteins that bind HSA with high specificity and affinity, but the biological consequences of these proteinprotein interactions are poorly understood. Group G streptococci (GGS), carrying the HSA-binding protein G, colonize the skin and the mucosa of the upper respiratory tract, mostly without causing disease. In the case of bacterial invasion, proinflammatory cytokines are released that activate the epithelium to produce antibacterial peptides, in particular the chemokine MIG/CXCL9. In addition, the inflammation causes capillary leakage and extravasation of HSA and other plasma proteins, environmental changes at the epithelial surface to which the bacteria need to respond. In this study, we found that GGS adsorbed HSA from both saliva and plasma via binding to protein G and that HSA bound to protein G bound and inactivated the antibacterial MIG/CXCL9 peptide. Another surface protein of GGS, FOG, was found to mediate adherence of the bacteria to pharyngeal epithelial cells through interaction with glycosaminoglycans. This adherence was not affected by activation of the epithelium with a combination of IFN-␥ and TNF-␣, leading to the production of MIG/CXCL9. However, at the activated epithelial surface, adherent GGS were protected against killing by MIG/CXCL9 through protein Gdependent HSA coating. The findings identify a previously unknown bacterial survival strategy that helps to explain the evolution of HSA-binding proteins among bacterial species of the normal human microbiota.

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“…An IDR-1 derivative, IDR-1002, showed stronger protective activity in vitro and in mouse models of infection with S. aureus and E. coli (Nijnik et al, 2010). Another promising new molecule currently under investigation is novicidin, a linear cationic -helical AMP derived from ovispirin, a cationic peptide originated from the ovine cathelicidin SMAP-29 (Dorosz et al, 2010). A bovine cathelicidin with broad-spectrum activity, termed indolicidin, was originally isolated from bovine neutrophils (Selsted et al, 1992).…”

Section: Mammalian Cathelicidinsmentioning

confidence: 99%