The Anticancer Peptide TAT-RasGAP317-326 Exerts Broad Antimicrobial Activity.

Mathieu Heulot,Didier Le Roy,Nicolas Jacquier,Evgeniya Trofimenko,Thierry Roger,David Barras,Gilbert Greub,Christian Widmann,Sébastien Aeby

doi:10.3389/fmicb.2017.00994

Abstract

Antibiotic resistance has become a major health issue. Nosocomial infections and the prevalence of resistant pathogenic bacterial strains are rising steadily. Therefore, there is an urgent need to develop new classes of antibiotics effective on multi-resistant nosocomial pathogenic bacteria. We have previously shown that a cell-permeable peptide derived from the p120 Ras GTPase-activating protein (RasGAP), called TAT-RasGAP317−326, induces cancer cell death, inhibits metastatic progression, and sensitizes tumor cells to various anti-cancer treatments in vitro and in vivo. We here report that TAT-RasGAP317−326 also possesses antimicrobial activity. In vitro, TAT-RasGAP317−326, but not mutated or truncated forms of the peptide, efficiently killed a series of bacteria including Escherichia coli, Acinetobacter baumannii, Staphylococcus aureus, and Pseudomonas aeruginosa. In vivo experiments revealed that TAT-RasGAP317−326 protects mice from lethal E. coli-induced peritonitis if administrated locally at the onset of infection. However, the protective effect was lost when treatment was delayed, likely due to rapid clearance and inadequate biodistribution of the peptide. Peptide modifications might overcome these shortcomings to increase the in vivo efficacy of the compound in the context of the currently limited antimicrobial options.

Highlights

A first line of defense provided by the innate immune system of multicellular organisms relies on the production of antimicrobial peptides
During an episode of contamination of mammalian cell cultures, we observed that the growth of an initially uncharacterized microorganism was prevented when the culture medium contained the TAT-RasGAP317−326 peptide (Figure 1A)
There is an urgent need for new antimicrobial agents to treat the increasing numbers of patients suffering from life-threatening infections due to multi-drug resistant Gram-negative and Gram-positive bacteria

Summary

Introduction

A first line of defense provided by the innate immune system of multicellular organisms relies on the production of antimicrobial peptides. Antimicrobial peptides are composed of 10–50 amino-acid residues and classified into different categories based on their amino-acid composition, size, and conformation (Nakatsuji and Gallo, 2012) They lack any obvious specific consensus amino-acid sequences associated with biological activity; yet most of them maintain certain common features, such as the presence of positively charged amino-acids. It is recognized that antimicrobial peptides can compromise bacterial viability independently of their action on membrane permeability, inhibiting for example protein or cell wall synthesis (Guilhelmelli et al, 2013). Rather surprisingly, despite their well-documented anti-bacterial properties, antimicrobial peptides have poorly attracted the interest of antibiotic producers that have rather focused on the development of small synthetic anti-bacterial molecules. With the emergence of antibiotic resistance against small antibiotic molecules and the steady decline in the discovery and release of new antibiotics, antimicrobial peptides hold the potential to provide an alternative source of potent antimicrobial agents (Chan et al, 2006)

Methods

Results

Conclusion