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J Biol Chem. 2019 May 10;294(19):7615-7631. doi: 10.1074/jbc.RA118.006968. Epub 2019 Mar 20.

A small mycobacteriophage-derived peptide and its improved isomer restrict mycobacterial infection via dual mycobactericidal-immunoregulatory activities.

Author information

1
From the Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, Jiangsu.
2
the Key Laboratory of Animal Models and Human Disease Mechanisms, Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming 650223, Yunnan.
3
the National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, Wuxi 214064, Jiangsu Province.
4
the Institute of Pharmaceutical Biotechnology and Engineering, College of Biological Science and Technology, Fuzhou University, Fuzhou 350108, and.
5
the School of Basic Medical Sciences, Kunming Medical University, Kunming 650500, Yunnan, China.
6
the Key Laboratory of Animal Models and Human Disease Mechanisms, Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming 650223, Yunnan, rlai@mail.kiz.ac.cn.
7
From the Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, Jiangsu, xuweifd828@126.com.
8
From the Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, Jiangsu, weilin1005@126.com.

Abstract

Mycobacteriophages express various peptides/proteins to infect Mycobacterium tuberculosis (M. tb). Particular attention has been paid to mycobacteriophage-derived endolysin proteins. We herein characterized a small mycobacteriophage-derived peptide designated AK15 with potent anti-M. tb activity. AK15 adopted cationic amphiphilic α-helical structure, and on the basis of this structure, we designed six isomers with increased hydrophobic moment by rearranging amino acid residues of the helix. We found that one of these isomers, AK15-6, exhibits enhanced anti-mycobacterial efficiency. Both AK15 and AK15-6 directly inhibited M. tb by trehalose 6,6'-dimycolate (TDM) binding and membrane disruption. They both exhibited bactericidal activity, cell selectivity, and synergistic effects with rifampicin, and neither induced drug resistance to M. tb They efficiently attenuated mycobacterial load in the lungs of M. tb-infected mice. We observed that lysine, arginine, tryptophan, and an α-helix are key structural requirements for their direct anti-mycobacterial action. Of note, they also exhibited immunomodulatory effects, including inhibition of proinflammatory response in TDM-stimulated or M. tb-infected murine bone marrow-derived macrophages (BMDMs) and M.tb-infected mice and induction of only a modest level of cytokine (tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6)) production in murine BMDMs and a T-cell cytokine (interferin-γ (IFN-γ) and TNF-α) response in murine lung and spleen. In summary, characterization of a small mycobacteriophage-derived peptide and its improved isomer revealed that both efficiently restrain M. tb infection via dual mycobactericidal-immunoregulatory activities. Our work provides clues for identifying small mycobacteriophage-derived anti-mycobacterial peptides and improving those that have cationic amphiphilic α-helices.

KEYWORDS:

Mycobacterium tuberculosis; amino acid; anti-mycobacterial peptide; antibiotic; antimicrobial peptide (AMP); drug action; drug resistance; endolysin; hydrophobic moment; immune regulation; mycobacteriophage; peptides; structure-function; α-helix

PMID:
30894414
PMCID:
PMC6514635
[Available on 2020-05-10]
DOI:
10.1074/jbc.RA118.006968

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