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.
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 2x10(10) colony-forming units of E. coli E79466. Following bacterial challenge, all animals were randomised to receive i.p. administration of saline, 40mg/kg ceftazidime (CAZ), or 40mg/kg CAZ+s-thanatin (10, 20 or 40mg/kg). The results showed that s-thanatin not only completely bound to the LPS (median effective concentration of 17.5microg/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.
Wu
Guoqiu
G
Center of Clinical Laboratory Medicine of Zhongda Hospital, Southeast University, 87 Dingjiaqiao, Nanjing 210009, China. nationball@163.com
Fan
Xiaobo
X
Li
Linxian
L
Wang
Hailiang
H
Ding
Jiaxuan
J
Hongbin
Wu
W
Zhao
Rui
R
Gou
Lixia
L
Shen
Zilong
Z
Xi
Tao
T
D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism* / Q000627:therapeutic use*; D001202:Ascitic Fluid / Q000382:microbiology; D001769:Blood / Q000382:microbiology; D015169:Colony Count, Microbial; D024901:Drug Resistance, Multiple, Bacterial; D004731:Endotoxins / Q000097:blood; D004926:Escherichia coli / Q000187:drug effects; D004927:Escherichia coli Infections / Q000188:drug therapy*; D007274:Injections, Intraperitoneal; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D050296:Microbial Viability; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use*; D011485:Protein Binding; D012772:Shock, Septic / Q000188:drug therapy*; D016019:Survival Analysis
D023181:Antimicrobial Cationic Peptides; D004731:Endotoxins; D008070:Lipopolysaccharides; D010456:Peptides, Cyclic; C098076:thanatin