Synthetic Antibiotic Derived from Sequences Encrypted in a Protein from Human Plasma

被引：32

作者：

Cesaro, Angela ^{[1
,2
,3
,4
,5
,6
,7
]}

Torres, Marcelo D. T. ^{[8
]}

Gaglione, Rosa ^{[1
,9
]}

Dell'Olmo, Eliana ^{[1
]}

Di Girolamo, Rocco ^{[1
]}

Bosso, Andrea ^{[10
]}

Pizzo, Elio ^{[10
]}

Haagsman, Henk P. ^{[2
]}

Veldhuizen, Edwin J. A. ^{[2
]}

de la Fuente-Nunez, Cesar ^{[3
,4
,5
,6
,7
,8
]}

Arciello, Angela ^{[1
,9
]}

机构：

[1] Univ Naples Federico II, Dept Chem Sci, I-80126 Naples, Italy

[2] Univ Utrecht, Fac Vet Med, Div Infect Dis & Immunol, Sect Mol Host Def,Dept Biomol Hlth Sci, NL-3584 CL Utrecht, Netherlands

[3] Univ Penn, Perelman Sch Med, Machine Biol Grp, Dept Psychiat,Inst Biomed Informat,Inst Translat, Philadelphia, PA 19104 USA

[4] Univ Penn, Perelman Sch Med, Machine Biol Grp, Dept Microbiol,Inst Biomed Informat,Inst Translat, Philadelphia, PA 19104 USA

[5] Univ Penn, Dept Bioengn, Sch Engn & Appl Sci, Philadelphia, PA 19104 USA

[6] Univ Penn, Dept Chem, Sch Engn & Appl Sci, Philadelphia, PA 19104 USA

[7] Univ Penn, Dept Biomol Engn, Sch Engn & Appl Sci, Philadelphia, PA 19104 USA

[8] Univ Penn, Penn Inst Computat Sci, Philadelphia, PA 19104 USA

[9] Ist Nazl Biostrutture & Biosistemi INBB, I-00136 Rome, Italy

[10] Univ Naples Federico II, Dept Biol, I-80126 Naples, Italy

来源：

ACS NANO | 2022年 / 16卷 / 02期

基金：

美国国家卫生研究院;

关键词：

encrypted peptides; human apolipoprotein B; antibiotic resistance; drug discovery; retro-inverso peptide design; anti-infective activity; nanopeptides; PSEUDOMONAS-AERUGINOSA; ANTIMICROBIAL PEPTIDES; DECORALIN ANALOGS; CRYPTIC PEPTIDES; ANTIBACTERIAL; RESISTANCE; STABILITY; BIOFILMS;

D O I：

10.1021/acsnano.1c04496

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Encrypted peptides have been recently found in the human proteome and represent a potential class of antibiotics. Here we report three peptides derived from the human apolipoprotein B (residues 887-922) that exhibited potent antimicrobial activity against drug-resistant Klebsiella pneumoniae, Acinetobacter baumannii, and Staphylococci both in vitro and in an animal model. The peptides had excellent cytotoxicity profiles, targeted bacteria by depolarizing and permeabilizing their cytoplasmic membrane, inhibited biofilms, and displayed anti-inflammatory properties. Importantly, the peptides, when used in combination, potentiated the activity of conventional antibiotics against bacteria and did not select for bacterial resistance. To ensure translatability of these molecules, a protease resistant retro-inverso variant of the lead encrypted peptide was synthesized and demonstrated anti-infective activity in a preclinical mouse model. Our results provide a link between human plasma and innate immunity and point to the blood as a source of much-needed antimicrobials.

引用

页码：1880 / 1895

页数：16

共 74 条

[11] Inhibition of Bacterial Biofilm Formation and Swarming Motility by a Small Synthetic Cationic Peptide [J].