title: R-thanatin inhibits growth and biofilm formation of methicillin-resistant Staphylococcus epidermidis in vivo and in vitro.
abstract: Staphylococcus epidermidis is one of the most frequent causes of device-associated infections, because it is known to cause biofilms that grow on catheters or other surgical implants. The persistent increasing resistance of S. epidermidis and other coagulase-negative staphylococci (CoNS) has driven the need for newer antibacterial agents with innovative therapeutic strategies. Thanatin is reported to display potent antibiotic activities, especially against extended-spectrum-beta-lactamase-producing Escherichia coli. The present study aimed to investigate whether a shorter derivative peptide (R-thanatin) could be used as a novel antibacterial agent. We found that R-thanatin was highly potent in vitro against coagulase-negative staphylococci, such as S. epidermidis, S. haemolyticus, and S. hominis, and inhibited biofilm formation at subinhibitory concentrations. Properties of little toxicity to human red blood cells (hRBCs) and human umbilical vein endothelial cells, a low incidence of resistance, and relatively high stability in plasma were confirmed. Excellent in vivo protective effects were also observed using a methicillin-resistant S. epidermidis (MRSE)-induced urinary tract infection rat model. Electron microscopy and confocal laser-scanning microscopy analyses suggested that R-thanatin disturbed cell division of MRSE severely, which might be the reason for inhibition of MRSE growth. These findings indicate that R-thanatin is active against the growth and biofilm formation of MRSE in vitro and in vivo. R-thanatin might be considered as a specific drug candidate for treating CoNS infections.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Hou
authors.forename: Fei
authors.initials: F
authors.lastname: Da
authors.forename: Baohui
authors.initials: B
authors.lastname: Liu
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Xue
authors.forename: Xiuli
authors.initials: X
authors.lastname: Xu
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.forename: Mingkai
authors.initials: M
authors.lastname: Li
authors.forename: Zhi
authors.initials: Z
authors.lastname: Li
authors.forename: Xue
authors.initials: X
authors.lastname: Ma
authors.forename: Jingru
authors.initials: J
authors.lastname: Meng
authors.forename: Min
authors.initials: M
authors.lastname: Jia
authors.forename: Yukun
authors.initials: Y
authors.lastname: Wang
authors.forename: Xiaoxing
authors.initials: X
authors.lastname: Luo
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology* / Q000627:therapeutic use; D018441:Biofilms / Q000187:drug effects*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development; D008826:Microbial Sensitivity Tests; D051381:Rats; D013203:Staphylococcal Infections / Q000188:drug therapy
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; C098076:thanatin
references.citation: J Biol Chem. 2005 Sep 23;280(38):32921-9
references.pmid: 15894545
references.citation: Biomaterials. 2005 Nov;26(33):6530-5
references.pmid: 15949842
references.citation: Proc Natl Acad Sci U S A. 1996 Feb 6;93(3):1221-5
references.pmid: 8577744
references.citation: Nat Biotechnol. 2007 Jun;25(6):657-9
references.pmid: 17529972
references.citation: J Antimicrob Chemother. 2005 Oct;56(4):794-5
references.pmid: 16141281
references.citation: Antimicrob Agents Chemother. 2002 Mar;46(3):689-94
references.pmid: 11850249
references.citation: J Biol Chem. 2002 May 10;277(19):16941-51
references.pmid: 11847217
references.citation: J Antimicrob Chemother. 2007 Mar;59(3):493-8
references.pmid: 17289767
references.citation: Curr Opin Pharmacol. 2006 Oct;6(5):468-72
references.pmid: 16890021
references.citation: Antimicrob Agents Chemother. 2006 Apr;50(4):1463-9
references.pmid: 16569866
references.citation: J Microbiol Methods. 2000 Apr;40(2):175-9
references.pmid: 10699673
references.citation: Protein Sci. 1993 Oct;2(10):1574-90
references.pmid: 8251933
references.citation: J Infect Dis. 2011 Jan 15;203(2):273-82
references.pmid: 21288828
references.citation: Antimicrob Agents Chemother. 2011 Jul;55(7):3588-90
references.pmid: 21537028
references.citation: Curr Protoc Pharmacol. 2006 Jan;Chapter 13:Unit13A.3
references.pmid: 21953398
references.citation: PLoS One. 2010 Jul 29;5(7):e11841
references.pmid: 20686601
references.citation: Nat Rev Microbiol. 2007 Sep;5(9):727-40
references.pmid: 17703227
references.citation: AAPS J. 2013 Jan;15(1):132-42
references.pmid: 23135925
references.citation: Antimicrob Agents Chemother. 2007 Dec;51(12):4518-20
references.pmid: 17875996
references.citation: J Antimicrob Chemother. 2000 Mar;45(3):285-93
references.pmid: 10702546
references.citation: J Antimicrob Chemother. 2010 Nov;65(11):2336-40
references.pmid: 20852270
references.citation: Lancet. 1991 Jan 5;337(8732):54
references.pmid: 1670676
references.citation: Infect Genet Evol. 2011 Mar;11(2):446-53
references.pmid: 21172458
references.citation: Methods Mol Biol. 1997;78:133-50
references.pmid: 9276302
references.citation: Int J Antimicrob Agents. 2006 Aug;28 Suppl 1:S14-20
references.pmid: 16829054
references.citation: Nat Rev Drug Discov. 2011 Dec 16;11(1):37-51
references.pmid: 22173434
references.citation: Infect Immun. 2005 Mar;73(3):1856-60
references.pmid: 15731088
references.citation: Antimicrob Agents Chemother. 2005 Jun;49(6):2412-20
references.pmid: 15917541
references.citation: Acta Biomater. 2010 Mar;6(3):1119-24
references.pmid: 19733265
references.citation: Curr Microbiol. 2002 Jun;44(6):385-90
references.pmid: 12000986
references.citation: Nat Biotechnol. 2006 Dec;24(12):1551-7
references.pmid: 17160061
references.citation: Braz J Infect Dis. 2007 Jun;11(3):345-50
references.pmid: 17684637
references.citation: Proc Natl Acad Sci U S A. 2004 May 11;101(19):7363-8
references.pmid: 15118082