On Mar 20, 2019, researchers at Dr. Xu’s group published an article entitled “A small mycobacteriophage-derived peptide and its improved isomer restrict mycobacterial infection via dual mycobactericidal-immunoregulatory activities” in J Biol Chem.
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 none induced drug resistance to M. tb. They efficiently attenuated mycobacterial load in the lung 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.
Yang Yang, Zhen Liu, and Xiaoqin He are co-first authors. Min Li, Qian Qian, ect. are contributing authors. Dr. Wei Xu, Lin Wei and Ren Lai are co-corresponding authors. This work was supported by a Project Funded by National Natural Science Foundation of China (81402830, 31870868, 81603080, 31670930), China Postdoctoral Science Foundation (2015M571815), Natural Science Foundation of Jiangsu Province (BK20140362).