Interaction of antimicrobial peptide s-thanatin with lipopolysaccharide in vitro and in an experimental mouse model of septic shock caused by a multidrug-resistant clinical isolate of Escherichia coli

Abstract

s-thanatin, an analogue of thanatin, was synthesised by substituting the fifteenth amino acid threonine with serine and showed broad antimicrobial activity against Gram-negative and Gram-positive bacteria. To evaluate its antimicrobial activity against a multidrug-resistant (MDR) clinical isolate as well as its anti-endotoxin activity, its lipopolysaccharide (LPS)-binding and -neutralising activity in vitro and its therapeutic efficacy in an experimental model of septic shock caused by a MDR clinical isolate of Escherichia coli were studied. The ability of s-thanatin to bind or neutralise LPS from E. coli O111:B4 was determined using a quantitative assay kit. Male ICR mice were given an intraperitoneal (i.p.) administration of 2 × 10 10 colony-forming units of E. coli E79466. Following bacterial challenge, all animals were randomised to receive i.p. administration of saline, 40 mg/kg ceftazidime (CAZ), or 40 mg/kg CAZ + s-thanatin (10, 20 or 40 mg/kg). The results showed that s-thanatin not only completely bound to the LPS (median effective concentration of 17.5 μg/mL) but also improved the survival and reduced the number of inoculated bacteria in a mouse model of septic shock. s-thanatin may be an attractive candidate to develop as an anti-MDR bacterial agent.