title: N-Lipidated Peptide Dimers: Effective Antibacterial Agents against Gram-Negative Pathogens through Lipopolysaccharide Permeabilization.
abstract: Treating infections caused by multidrug-resistant Gram-negative pathogens is challenging, and there is concern regarding the toxicity of the most effective antimicrobials for Gram-negative pathogens. We hypothesized that conjugating a fatty acid moiety onto a peptide dimer could maximize the interaction with lipopolysaccharide (LPS) and facilitate the permeabilization of the LPS barrier, thereby improving potency against Gram-negative pathogens. We systematically designed a series of N-lipidated peptide dimers that are active against Gram-negative bacteria, including carbapenem-resistant Enterobacteriaceae (CRE). The optimized lipid length was 6-10 carbons. At these lipid lengths, the N-lipidated peptide dimers exhibited strong LPS permeabilization. Compound 23 exhibited synergy with select antibiotics in most of the combinations tested. 23 and 32 also displayed rapid bactericidal activity. Importantly, 23 and 32 were nonhemolytic at 10 mg/mL, with no cellular or in vivo toxicity. These characteristics suggest that these compounds can overcome the limitations of current Gram-negative-targeted antimicrobials such as polymyxin B.
authors.affiliation: Singapore Eye Research Institute, The Academia , 20 College Road, Discovery Tower Level 6, 169856, Singapore.|Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore , 119074, Singapore.
authors.forename: Jun-Jie
authors.initials: JJ
authors.lastname: Koh
authors.affiliation: Singapore Eye Research Institute, The Academia , 20 College Road, Discovery Tower Level 6, 169856, Singapore.
authors.forename: Huifen
authors.initials: H
authors.lastname: Lin
authors.affiliation: Singapore Eye Research Institute, The Academia , 20 College Road, Discovery Tower Level 6, 169856, Singapore.
authors.forename: Vonny
authors.initials: V
authors.lastname: Caroline
authors.affiliation: Singapore Eye Research Institute, The Academia , 20 College Road, Discovery Tower Level 6, 169856, Singapore.
authors.forename: Yu Siang
authors.initials: YS
authors.lastname: Chew
authors.affiliation: Singapore Eye Research Institute, The Academia , 20 College Road, Discovery Tower Level 6, 169856, Singapore.
authors.forename: Li Mei
authors.initials: LM
authors.lastname: Pang
authors.affiliation: Singapore Eye Research Institute, The Academia , 20 College Road, Discovery Tower Level 6, 169856, Singapore.
authors.forename: Thet Tun
authors.initials: TT
authors.lastname: Aung
authors.affiliation: Singapore Eye Research Institute, The Academia , 20 College Road, Discovery Tower Level 6, 169856, Singapore.|Bioinformatics Institute (A*STAR) , 30 Biopolis Street, 07-01 matrix, 138671, Singapore.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Li
authors.affiliation: Singapore Eye Research Institute, The Academia , 20 College Road, Discovery Tower Level 6, 169856, Singapore.|SRP Neuroscience and Behavioural Disorders, Duke-NUS Medical School , 169857, Singapore.
authors.forename: Rajamani
authors.initials: R
authors.lastname: Lakshminarayanan
authors.affiliation: Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore , 119074, Singapore.|Singapore National Eye Centre , 11 Third Hospital Avenue, 168751, Singapore.
authors.forename: Donald T H
authors.initials: DT
authors.lastname: Tan
authors.affiliation: Singapore Eye Research Institute, The Academia , 20 College Road, Discovery Tower Level 6, 169856, Singapore.|Bioinformatics Institute (A*STAR) , 30 Biopolis Street, 07-01 matrix, 138671, Singapore.|School of Biological Sciences, Nanyang Technological University , 60 Nanyang Drive, 637551, Singapore.|Department of Biological Sciences, National University of Singapore , 14 Science Drive 4, 117543, Singapore.
authors.forename: Chandra
authors.initials: C
authors.lastname: Verma
authors.affiliation: Department of Pathology, Singapore General Hospital , 169608, Singapore.
authors.forename: Ai Ling
authors.initials: AL
authors.lastname: Tan
authors.affiliation: Singapore Eye Research Institute, The Academia , 20 College Road, Discovery Tower Level 6, 169856, Singapore.|SRP Neuroscience and Behavioural Disorders, Duke-NUS Medical School , 169857, Singapore.
authors.forename: Roger W
authors.initials: RW
authors.lastname: Beuerman
authors.affiliation: Singapore Eye Research Institute, The Academia , 20 College Road, Discovery Tower Level 6, 169856, Singapore.|SRP Neuroscience and Behavioural Disorders, Duke-NUS Medical School , 169857, Singapore.
authors.forename: Shouping
authors.initials: S
authors.lastname: Liu
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D015780:Carbapenems / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects; D002470:Cell Survival; D024881:Drug Resistance, Bacterial; D004755:Enterobacteriaceae / Q000187:drug effects; D005227:Fatty Acids / Q000737:chemistry; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D055666:Lipopeptides / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D008070:Lipopolysaccharides / Q000378:metabolism*; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D010539:Permeability; D011817:Rabbits
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D005227:Fatty Acids; D055666:Lipopeptides; D008070:Lipopolysaccharides; D007770:L-Lactate Dehydrogenase