A novel antimicrobial peptide significantly enhances acid-induced killing of Shiga toxin-producing Escherichia coli O157 and non-O157 serotypes

Abstract

Shiga toxin-producing Escherichia coli (STEC) colonizes the human intestine, causing haemorrhagic colitis and haemolytic uraemic syndrome (HUS). Treatment options are limited to intravenous fluids in part because sublethal doses of some antibiotics have been shown to stimulate increased toxin release and enhance the risk of progression to HUS. Preventative antimicrobial agents, especially those that build on the natural antimicrobial action of the host defence, may provide a better option. In order to survive the acid stress of gastric passage, STEC is equipped with numerous acid resistance and DNA repair mechanisms. Inhibition of acid-induced DNA repair may offer a strategy to target survival of ingested STEC. We report here that brief pretreatment with a novel antimicrobial peptide, which was previously shown to inhibit bacterial DNA repair, significantly and profoundly reduces survival of acid-stressed O157 : H7 and non-O157 : H7 STEC seropathotypes that are highly associated with HUS. Reduction in survival rates of STEC range from 3 to 5 log. We also show that peptide/acid treatment results in little or no increase in toxin production, thereby reducing the risk of progression to HUS. This study identifies the peptide wrwycr as a potential new candidate for a preventative antimicrobial for STEC infection.

Escherichia coli enterobactin synthesis and uptake mutants are hypersensitive to an antimicrobial peptide that limits the availability of iron in addition to blocking Holliday junction resolution

“…Because mammalian host defences such as gastric acid and the oxidative burst in macrophages induce DNA damage and thus DNA repair in bacterial invaders, use of wrwycr in antimicrobial therapy may increase the efficacy of these natural defence systems. Recently, wrwycr was shown to inhibit the growth of Salmonella enterica serovar Typhimurium inside macrophages (Su et al, 2010) and significantly enhance acid-induced killing of Shiga toxin-producing strains of Escherichia coli associated with haemolytic uraemia syndrome (Lino et al, 2011).…”

Novel antimicrobial peptide prevents C. rodentium infection in C57BL/6 mice by enhancing acid-induced pathogen killing

“…We previously demonstrated that pretreatment of EHEC with wrwycr followed by acid stress similar to that of gastric acid profoundly decreases the survival of EHEC seropathotypes that are highly associated with HUS (Lino et al, 2011). Furthermore, acid-induced EHEC killing was dose dependent with peptide concentration.…”

“…These intermediate structures must be fully resolved in order for DNA repair to proceed. Failure to resolve these structures is lethal to the bacteria (Lino et al, 2011). If acid-induced DNA damage repair is ablated through inhibition of HJ resolution, this would compromise EHEC survival and thereby decrease the potential for EHEC infection of the GI tract.…”

“…Many of the effects of the peptide are similar to those of a small molecule, TPI1609-10 (Yitzhaki et al, 2012. Consequently, wrwycr is a potent, broad-spectrum antimicrobial able to inhibit bacterial growth in a dose-dependent manner with both intracellular and membrane targets (Gunderson & Segall, 2006;Lino et al, 2011;Su et al, 2010).…”

“…The most common and severe type of stress is the extreme acidity in the stomach, followed by weak acid stress in the upper GI tract (Lin et al, 1996;Lino et al, 2011;Thorpe, 2004).…”