RT Journal Article
T1 Design, synthesis and structure-activity relationship (SAR) studies of an unusual class of non-cationic fatty amine-tripeptide conjugates as novel synthetic antimicrobial agents
A1 Hernández Ortiz, Noelia
A1 Sánchez-Murcia, Pedro A.
A1 Gil Campillo, Celia
A1 Domenech Lucas, Miriam
A1 Lucena Agell, Daniel
A1 Hortigüela, Rafael
A1 Velázquez, Sonsoles
A1 Camarasa, María José
A1 Bustamante, Noemí
A1 Castro, Sonia de
A1 Menéndez, Margarita
AB Cationic ultrashort lipopeptides (USLPs) are promising antimicrobial candidates to combat multidrug-resistant bacteria. Using DICAMs, a newly synthesized family of tripeptides with net charges from −2 to +1 and a fatty amine conjugated to the C-terminus, we demonstrate that anionic and neutral zwitterionic USLPs can possess potent antimicrobial and membrane-disrupting activities against prevalent human pathogens such as Streptococcus pneumoniae and Streptococcus pyogenes. The strongest antimicrobials completely halt bacterial growth at low micromolar concentrations, reduce bacterial survival by several orders of magnitude, and may kill planktonic cells and biofilms. All of them comprise either an anionic or neutral zwitterionic peptide attached to a long fatty amine (16–18 carbon atoms) and show a preference for anionic lipid membranes enriched in phosphatidylglycerol (PG), which excludes electrostatic interactions as the main driving force for DICAM action. Hence, the hydrophobic contacts provided by the long aliphatic chains of their fatty amines are needed for DICAM’s membrane insertion, while negative-charge shielding by salt counterions would reduce electrostatic repulsions. Additionally, we show that other components of the bacterial envelope, including the capsular polysaccharide, can influence the microbicidal activity of DICAMs. Several promising candidates with good-to-tolerable therapeutic ratios are identified as potential agents against S. pneumoniae and S. pyogenes. Structural characteristics that determine the preference for a specific pathogen or decrease DICAM toxicity have also been investigated.
PB Frontiers Media
SN 1663-9812
YR 2024
FD 2024-08-02
LK https://hdl.handle.net/20.500.14352/117673
UL https://hdl.handle.net/20.500.14352/117673
LA eng
NO Hernández-Ortiz, N., Sánchez-Murcia, P. A., Gil-Campillo, C., Domenech, M., Lucena-Agell, D., Hortigüela, R., Velázquez, S., Camarasa, M. J., Bustamante, N., de Castro, S., & Menéndez, M. (2024). Design, synthesis and structure-activity relationship (SAR) studies of an unusual class of non-cationic fatty amine-tripeptide conjugates as novel synthetic antimicrobial agents. Frontiers in Pharmacology, 15. https://doi.org/10.3389/FPHAR.2024.1428409
NO Ministerio de Ciencia, Innovación y Universidades (España)
NO Instituto de Salud Carlos III
NO Consejo Superior de Investigaciones Científicas (España)
DS Docta Complutense
RD 18 abr 2025