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

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.

Antimicrobial Peptides as Anticancer Agents: Functional Properties and Biological Activities

“…This peptide can induce cancer cell death directly without inducing apoptosis. TAT-RasGAP317−326 inhibits metastatic progression [ 116 ].…”

The antimicrobial peptide TAT-RasGAP317-326inhibits the formation and the expansion of bacterial biofilmsin vitro

“…We need to test in future studies the anti-biofilm effect of combinations of TAT-RasGAP317-326 with classical antibiotics. Indeed, TAT-RasGAP317-326 might have advantages compared to other AMPs: its quite low toxicity to mammalian cells [20] and its chimeric nature against which bacteria should not have developed resistance. Moreover, since biofilms are often composed of multiple bacterial species, the broad-spectrum antimicrobial activity of TAT-RasGAP317-326 is interesting for future clinical developments.…”

“…Moreover, since biofilms are often composed of multiple bacterial species, the broad-spectrum antimicrobial activity of TAT-RasGAP317-326 is interesting for future clinical developments. The current limitation of TAT-RasGAP317-326 for clinical use is its high excretion rate and subsequent low bioavailability [20]. We thus need to develop strategies to increase the distribution of this peptide in vivo, which could be achieved by chemical modifications or specific delivery methods.…”

“…TAT-RasGAP317-326 was first described for its anticancer properties, being able to sensitise cancer cells to anticancer therapies [15][16][17], directly kill cancer cells [18] and display anti-metastatic effect [19]. More recently, we showed that TAT-RasGAP317-326 exerts a broad antimicrobial activity against both Gram-positive and Gram-negative human pathogens including A. baumannii, P. aeruginosa and S. aureus [20]. Like other AMPs, TAT-RasGAP317-326 is positively charged and contains several arginine and tryptophan residues.…”

“…TAT-RasGAP317-326 has an effect on both Gram-negative and Gram-positive bacteria in planktonic cultures [20]. We thus tested its impact on S. aureus biofilms.…”