An engineered multidomain bactericidal peptide as a model for targeted antibiotics against specific bacteria.
We constructed a peptide consisting of a staphylococcal AgrD1 pheromone fused to the channel-forming domain of colicin Ia and named it pheromonicin. This fusion peptide had bactericidal effects against methicillin-sensitive and methicillin-resistant Staphylococcus aureus (MSSA and MRSA, respectively), but not against Staphylococcus epidermidis or Streptococcus pneumoniae. Growth rates, vital staining and colony forming unit (CFU) counts showed that pheromonicin did not merely suppress growth but killed S. aureus cells. The specificity of pheromonicin was shown by the absence of bactericidal effects against an accessory gene regulator (agr) locus knockout of S. aureus, and a dose-dependent inhibition of the bactericidal effects of pheromonicin by competition with corresponding free AgrD pheromone. In vivo, all pheromonicin-treated mice survived administration of MRSA that was lethal to controls. No toxicity was detectable in human liver or renal cells in culture, or in livers, kidneys or spleens of pheromonicin-treated mice. The results suggest that these types of chimeric peptides may be of value as antibiotics against specific bacterial infections.
Qiu
Xiao-Qing
XQ
Laboratory of Transplant Immunology, West China Hospital, Sichuan University, No. 37 GuoXueXiang, Chengdu, Sichuan, China 610041. qiu@mrsa.com.cn
Wang
He
H
Lu
Xiao-Fong
XF
Zhang
Jie
J
Li
Sheng-Fu
SF
Cheng
Gang
G
Wan
Lin
L
Yang
Li
L
Zuo
Jun-Yong
JY
Zhou
Yu-Qi
YQ
Wang
Hai-Yun
HY
Cheng
Xin
X
Zhang
Su-Hua
SH
Ou
Zheng-Rong
ZR
Zhong
Zi-Cheng
ZC
Cheng
Jing-Qiu
JQ
Li
You-Ping
YP
Wu
George Y
GY
D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000096:biosynthesis* / Q000494:pharmacology*; D000918:Antibody Specificity / Q000502:physiology; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D002478:Cells, Cultured; D003087:Colicins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D010456:Peptides, Cyclic; D015202:Protein Engineering / Q000379:methods*; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000494:pharmacology; D012680:Sensitivity and Specificity; D013210:Staphylococcus / Q000145:classification / Q000187:drug effects*; D013291:Streptococcus / Q000187:drug effects*
C414532:AgrD protein, Staphylococcus; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D003087:Colicins; D010455:Peptides; D010456:Peptides, Cyclic; D011993:Recombinant Fusion Proteins