title: Antimicrobial activities and action mechanism studies of transportan 10 and its analogues against multidrug-resistant bacteria.
abstract: The increased emergence of multidrug-resistant bacteria is perceived as a critical public health threat, creating an urgent need for the development of novel classes of antimicrobials. Cell-penetrating peptides that share common features with antimicrobial peptides have been found to have antimicrobial activity and are currently being considered as potential alternatives to antibiotics. Transportan 10 is a chimeric cell-penetrating peptide that has been reported to transport biologically relevant cargoes into mammalian cells and cause damage to microbial membranes. In this study, we designed a series of TP10 analogues and studied their structure-activity relationships. We first evaluated the antimicrobial activities of these compounds against multidrug-resistant bacteria, which are responsible for most nosocomial infections. Our results showed that several of these compounds had potent antimicrobial and biofilm-inhibiting activities. We also measured the toxicity of these compounds, finding that Lys substitution could increase the antimicrobial activity but significantly enhanced the cytotoxicity. Pro introduction could reduce the cytotoxicity but disrupted the helical structure, resulting in a loss of activity. In the mechanistic studies, TP10 killed bacteria by membrane-active and DNA-binding activities. In conclusion, TP10 and its analogues could be developed into promising antibiotic candidates for the treatment of infections caused by multidrug-resistant bacteria.
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
authors.forename: Junqiu
authors.initials: J
authors.lastname: Xie
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
authors.forename: Yuanmei
authors.initials: Y
authors.lastname: Gou
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
authors.forename: Sisi
authors.initials: S
authors.lastname: Li
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Song
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
authors.forename: Lingyun
authors.initials: L
authors.lastname: Mou
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
authors.forename: Jingyi
authors.initials: J
authors.lastname: Li
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
authors.forename: Kairong
authors.initials: K
authors.lastname: Wang
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
authors.forename: Bangzhi
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
authors.forename: Wenle
authors.initials: W
authors.lastname: Yang
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects / Q000254:growth & development; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects / Q000254:growth & development; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects; D057846:Cell-Penetrating Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D004269:DNA, Bacterial / Q000037:antagonists & inhibitors* / Q000737:chemistry; D024901:Drug Resistance, Multiple, Bacterial / Q000502:physiology; D004912:Erythrocytes / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000254:growth & development; D011993:Recombinant Fusion Proteins / Q000138:chemical synthesis / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development; D013329:Structure-Activity Relationship; D014862:Wasp Venoms / Q000737:chemistry; D014863:Wasps
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D057846:Cell-Penetrating Peptides; D004269:DNA, Bacterial; D011993:Recombinant Fusion Proteins; D014862:Wasp Venoms; C586078:transportan-10
keywords: action mechanism; cell-penetrating peptides; multidrug-resistant bacteria; structure-activity relationships; transportan 10