%PDF-1.7
%
2 0 obj
<<
/Metadata 4 0 R
/Names 5 0 R
/Outlines 6 0 R
/Pages 7 0 R
/Type /Catalog
>>
endobj
4 0 obj
<<
/Length 5588
/Subtype /XML
/Type /Metadata
>>
stream
Reiner Noschka
Fanny Wondany
Gönül Kizilsavas
Tanja Weil
Gilbert Weidinger
Paul Walther
Jens Michaelis and Steffen Stenger
tuberculosis
antimicrobial peptide
Granulysin
human
macrophages
Granulysin is an antimicrobial peptide (AMP) expressed by human T-lymphocytes and natural killer cells. Despite a remarkably broad antimicrobial spectrum, its implementation into clinical practice has been hampered by its large size and off-target effects. To circumvent these limitations, we synthesized a 29 amino acid fragment within the putative cytolytic site of Granulysin (termed “Gran1”). We evaluated the antimicrobial activity of Gran1 against the major human pathogen Mycobacterium tuberculosis (Mtb) and a panel of clinically relevant non-tuberculous mycobacteria which are notoriously difficult to treat. Gran1 efficiently inhibited the mycobacterial proliferation in the low micro molar range. Super-resolution fluorescence microscopy and scanning electron microscopy indicated that Gran1 interacts with the surface of Mtb, causing lethal distortions of the cell wall. Importantly, Gran1 showed no off-target effects (cytokine release, chemotaxis, cell death) in primary human cells or zebrafish embryos (cytotoxicity, developmental toxicity, neurotoxicity, cardiotoxicity). Gran1 was selectively internalized by macrophages, the major host cell of Mtb, and restricted the proliferation of the pathogen. Our results demonstrate that the hypothesis-driven design of AMPs is a powerful approach for the identification of small bioactive compounds with specific antimicrobial activity. Gran1 is a promising component for the design of AMP-containing nanoparticles with selective activity and favorable pharmacokinetics to be pushed forward into experimental in vivo models of infectious diseases, most notably tuberculosis.
Gran1: A Granulysin-Derived Peptide with Potent Activity against Intracellular Mycobacterium tuberculosis
application/pdf
2021-08-05T03:55:49+02:00
LaTeX with hyperref
2021-08-10T11:32:23+02:00
tuberculosis; antimicrobial peptide; Granulysin; human; macrophages
pdfTeX-1.40.21
uuid:b7bd9264-f987-48cb-9f6c-bd4bef74f97e
uuid:a12e25b0-01e0-4c3a-b4e5-e55f5cc0c0ed
endstream
endobj
62 0 obj
<<
/Filter /FlateDecode
/Length 4665
>>
stream
xڭ[Y8~۲&J0q{<^z횝hD$<4"YLd=@D"/,[?~ d0JSLhuC_?_U`WL*B;8i!;ROͳOKBũOi(bel^`E2NZ;Pi~_ma
dNV
J"h@l ɘHLͳDxus
"rR$ZlWy/78=XDdJq>eL_u-Z^^Uۮ<^T]wš3ۂM+/ܙAF*N剿QEY>:V)2DW`=FWD7J^ޗMk|Le0SBK㿚6DDKH(Y" -K;B'Ӯt]ϫ$zN)\^LwRߴA$,WŔv1H$n|v7WRJOןt)":{6%\r7hk]q\-oN`jvk7B 7R(bC|S-{]f@e@W|3xg*3v~f9ıy!qezͮl*-|¡x]χES-P:I";<$Mq/L{,؏bМv 9(fa=bq,$.y#|Wӝidd%| _vl)g(r
}
s3"C#C9CQo28ij1v 00YlfSD;5lwWRexpZ6. (=Y|KXO.Ni1a՟j& [t[4aFRj8bqo
Д!7b4֑@O\bD6ᠷˌ0C%*
gDЏ"L49
\u|ouϷ 2ՙOUQ%Fsz
b2LNykزGYK)VFΤ0z?ktsdžk~*vFMeXGҊԽ:h}@g[a*Z>D`ty5]|AX
8<\U H63lvŢ`hP?>ںK:=̏3doxGƠe^اhڭ1RqS|3SīCGe~ c6}U3cl\j`{bi)%*sl^5ѣwBw9Wt4}qSÍT &͉~!a#tn"08,p~X5fldP/űk-xNf
Jz=5^s(jk[c^glMͦP Px}E{=oGD*Jar@#*loD$(]ACHGQ\FWIR$Y\OOʉ!h0tNhg(ȌXDmh[Bx;BDY_rD
() Go2kF-(d5
p#PEifwm3E]pG
'?{ 2K3?睯A+ `ղ)HH$YCc]֢&<6뾬ĶO>h
GHDi{p"@lnm´Pv"Ar*ə"θ>EJo[Kk|??:LѡT*-({PI:(c/