title: A mycobacteriophage-derived trehalose-6,6'-dimycolate-binding peptide containing both antimycobacterial and anti-inflammatory abilities.
abstract: Bacteriophages, the viruses of eubacteria, have developed unique mechanisms to interact with their host bacteria. They have been viewed as potential antibacterial therapeutics. Mycobacteriophage-derived compounds may interact with Mycobacterium tuberculosis (MTB) and/or its components, such as the cord factor, trehalose-6,6'-dimycolate (TDM), which is the most abundant glycolipid produced on the surface of MTB. TDM emulsion injected intravenously into mice induces lung immunopathology that mimics many aspects of MTB infection. Thus, TDM is an important target for anti-MTB agent development. On the basis of genomics information of mycobacteriophages, 200 peptides were synthesized. Their effects on MTB, their interactions with TDM, and anti-inflammatory activities were tested. One of them (PK34) showed MTB-killing activity with a minimal inhibitory concentration of 50 μg/ml and TDM-binding ability. In a mouse model, PK34 showed comparable ability to clear MTB as rifampin did in vivo. It also exerted strong activity to inhibit MTB or TDM-induced inflammation in vivo. PK34 significantly inhibited inflammatory cytokines secretions by inactivating MAPK and PKB signals while it maintained certain proinflammatory cytokine production. It is possible to prospect for TDM-binding and/or anti-MTB peptides by mining the mycobacteriophages genome. In addition to its direct MTB-killing ability, PK34 might be a useful adjunct in the treatment of granulomatous inflammation occurring during mycobacterial infection or a template for developing antituberculosis (TB) agents because of its immunoregulative effects. As a TDM-binding peptide, PK34 may be a promising tool to study TDM's interactions with corresponding receptors and signal pathways.
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms, Chinese Academy of Sciences and Yunan Province, Kunming Institute of Zoology, Kunming, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wei
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.forename: Han
authors.initials: H
authors.lastname: Liu
authors.forename: Hailong
authors.initials: H
authors.lastname: Yang
authors.forename: Mingqiang
authors.initials: M
authors.lastname: Rong
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Li
authors.forename: Pinghu
authors.initials: P
authors.lastname: Zhang
authors.forename: Junyou
authors.initials: J
authors.lastname: Han
authors.forename: Ren
authors.initials: R
authors.lastname: Lai
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism* / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000378:metabolism* / Q000494:pharmacology; D015153:Blotting, Western; D002460:Cell Line; D003311:Cord Factors / Q000378:metabolism* / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D005260:Female; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009160:Mycobacteriophages / Q000235:genetics / Q000378:metabolism*; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D010455:Peptides / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt; D012293:Rifampin / Q000494:pharmacology; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology
chemical_list: D000276:Adjuvants, Immunologic; D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D003311:Cord Factors; D016207:Cytokines; D010455:Peptides; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D012293:Rifampin
keywords: Mycobacterium tuberculosis; cord factor; cytokine; immunoregulative effects; mouse model