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The development of antimicrobial a-AApeptides that suppress proinflammatory immune responses.

ABSTRACT: Herein we describe the development of a new class of antimicrobial and anti-inflammatory peptidomimetics: cyclic lipo-?-AApeptides. They have potent and broad-spectrum antibacterial activity against a range of clinically relevant pathogens, including both multidrug-resistant Gram-positive and Gram-negative bacteria. Fluorescence microscopy suggests that cyclic lipo-?-AApeptides kill bacteria by disrupting bacterial membranes, possibly through a mechanism similar to that of cationic host-defense peptides (HDPs). Furthermore, the cyclic lipo-?-AApeptide can mimic cationic host-defense peptides by antagonizing Toll-like receptor 4 (TLR4) signaling responses and suppressing proinflammatory cytokines such as tumor necrosis factor-? (TNF-?). Our results suggest that by mimicking HDPs, cyclic lipo-?-AApeptides could emerge as a new class of antibiotic agents that directly kill bacteria, as well as novel antiinflammatory agents that act through immunomodulation.

SUBMITTER: Padhee S

PROVIDER: S-EPMC4043931 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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The development of antimicrobial a-AApeptides that suppress proinflammatory immune responses.

Padhee Shruti S Smith Christina C Wu Haifan H Li Yaqiong Y Manoj Namitha N Qiao Qiao Q Khan Zoya Z Cao Chuanhai C Yin Hang H Cai Jianfeng J

Chembiochem : a European journal of chemical biology 20140301 5

Herein we describe the development of a new class of antimicrobial and anti-inflammatory peptidomimetics: cyclic lipo-α-AApeptides. They have potent and broad-spectrum antibacterial activity against a range of clinically relevant pathogens, including both multidrug-resistant Gram-positive and Gram-negative bacteria. Fluorescence microscopy suggests that cyclic lipo-α-AApeptides kill bacteria by disrupting bacterial membranes, possibly through a mechanism similar to that of cationic host-defense ...[more]

PMID: 24677440

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Project description:IntroductionPrenatal exposures such as infections and immunisation may influence infant responses. We had an opportunity to undertake an analysis of innate responses in infants within the context of a study investigating the effects of maternal mycobacterial exposures and infection on BCG vaccine-induced responses in Ugandan infants.Material and methodsMaternal and cord blood samples from 29 mother-infant pairs were stimulated with innate stimuli for 24h and cytokines and chemokines in supernatants were measured using the Luminex® assay. The associations between maternal latent Mycobacterium tuberculosis infection (LTBI), maternal BCG scar (adjusted for each other's effect) and infant responses were examined using linear regression. Principal Component Analysis (PCA) was used to assess patterns of cytokine and chemokine responses. Gene expression profiles for pathways associated with maternal LTBI and with maternal BCG scar were examined using samples collected at one (n=42) and six (n=51) weeks after BCG immunisation using microarray.ResultsMaternal LTBI was positively associated with infant IP-10 responses with an adjusted geometric mean ratio (aGMR) [95% confidence interval (CI)] of 5.10 [1.21, 21.48]. Maternal BCG scar showed strong and consistent associations with IFN-γ (aGMR 2.69 [1.15, 6.17]), IL-12p70 (1.95 [1.10, 3.55]), IL-10 (1.82 [1.07, 3.09]), VEGF (3.55 [1.07, 11.48]) and IP-10 (6.76 [1.17, 38.02]). Further assessment of the associations using PCA showed no differences for maternal LTBI, but maternal BCG scar was associated with higher scores for principal component (PC) 1 (median level of scores: 1.44 in scar-positive versus -0.94 in scar-negative, p=0.020) in the infants. PC1 represented a controlled proinflammatory response. Interferon and inflammation response pathways were up-regulated in infants of mothers with LTBI at six weeks, and in infants of mothers with a BCG scar at one and six weeks after BCG immunisation.ConclusionsMaternal BCG scar had a stronger association with infant responses than maternal LTBI, with an increased proinflammatory immune profile.

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The development of antimicrobial a-AApeptides that suppress proinflammatory immune responses.

Publications

The development of antimicrobial a-AApeptides that suppress proinflammatory immune responses.

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