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Decoding the functional roles of cationic side chains of the major antimicrobial region of human cathelicidin LL-37.

ABSTRACT: Human cathelicidin LL-37 is a critical cationic antimicrobial peptide for host defense against infection, immune modulation, and wound healing. This article elucidates the functional roles of the cationic side chains of the major antimicrobial region of LL-37, corresponding to residues 17 to 32 (designated GF-17). Antimicrobial assays, killing kinetics studies, and vesicle leakage experiments all indicate that a conversion of lysines to arginines affected the ability of the peptide to kill the Gram-positive Staphylococcus aureus strain USA300. Alanine scanning experiments show that S. aureus is less sensitive than Escherichia coli to a single cationic residue mutation of GF-17. Among the five cationic residues, R23 appears to be somewhat important in killing S. aureus. However, R23 and K25 of GF-17 are of prime importance in killing the Gram-negative organism E. coli. In particular, R23 is essential for (i) rapid recognition, (ii) permeation of the E. coli outer membrane, (iii) clustering of anionic lipids in a membrane system mimicking the E. coli inner membrane, and (iv) membrane disruption. Bacterial aggregation (i.e., rapid recognition via charge neutralization) is the first step of the peptide action. Structurally, R23 is located in the interface (i.e., the first action layer), a situation ideal for the interactions listed above. In contrast, residues K18, R19, and R29 are on the hydrophilic surface of the amphipathic helix and play only a secondary role. Mapping of the functional spectrum of cationic residues of GF-17 provides a solid basis for engineering bacterium-specific antimicrobials using this highly potent template.

SUBMITTER: Wang G

PROVIDER: S-EPMC3264245 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Decoding the functional roles of cationic side chains of the major antimicrobial region of human cathelicidin LL-37.

Wang Guangshun G Epand Raquel F RF Mishra Biswajit B Lushnikova Tamara T Thomas Vinai Chittezham VC Bayles Kenneth W KW Epand Richard M RM

Antimicrobial agents and chemotherapy 20111114 2

Human cathelicidin LL-37 is a critical cationic antimicrobial peptide for host defense against infection, immune modulation, and wound healing. This article elucidates the functional roles of the cationic side chains of the major antimicrobial region of LL-37, corresponding to residues 17 to 32 (designated GF-17). Antimicrobial assays, killing kinetics studies, and vesicle leakage experiments all indicate that a conversion of lysines to arginines affected the ability of the peptide to kill the G ...[more]

PMID: 22083479

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Project description:BackgroundVitamin D insufficiency is common in industrialized and developing nations. Recent studies have shown that vitamin D insufficiency is associated with a higher risk of active tuberculosis. Laboratory studies provided a mechanism for this link on the basis of findings that vitamin D metabolites regulate the expression of cathelicidin (LL-37), which is an endogenous antimicrobial peptide with activity against Mycobacterium tuberculosis. Little information is available on the clinical relation between vitamin D, LL-37 concentrations, and disease severity in patients with tuberculosis.ObjectiveThe primary objective of the study was to evaluate the relation between vitamin D nutriture, serum LL-37 concentrations, and tuberculosis by using samples stored in the Tuberculosis Trials Consortium serum repository.DesignWe measured 25-hydroxyvitamin D [25(OH)D] and LL-37 concentrations in 95 serum specimens from patients with culture-confirmed pulmonary tuberculosis and correlated these concentrations to clinical and demographic variables.ResultsThe prevalence of vitamin D insufficiency [serum 25(OH)D concentration lt 30 ng/mL] in patients with active tuberculosis was 86% (n = 95) with a mean baseline serum 25(OH)D concentration of 20.4 ng/mL. Factors associated with vitamin D insufficiency were black race and indoor lifestyle. The mean ( plusmn SD) baseline LL-37 concentration was 49.5 plusmn 23.8 ng/mL. Higher LL-37 concentrations correlated with acid fast bacilli sputum smear positivity and weight gt 10% below ideal body weight. Serum vitamin D status of the study subjects did not correlate with serum LL-37 concentrations.ConclusionMore prospectively designed studies are needed to evaluate the clinical implications of vitamin D insufficiency in patients with tuberculosis and the utility of circulating LL-37 as a potential biomarker in patients with active tuberculosis disease. The parent trial was registered at clinicaltrials.gov as NCT00023335.

Dataset Information

Decoding the functional roles of cationic side chains of the major antimicrobial region of human cathelicidin LL-37.

Publications

Decoding the functional roles of cationic side chains of the major antimicrobial region of human cathelicidin LL-37.

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