A Natural Lipotrisaccharide and Its Derivatives Selectively Lyse Streptococcus pneumoniae via Interaction with Cell Membrane

A natural lipotrisaccharide (NP000778, 1a), a new triglycosidic tri-O-substituted glycolipid isolated from the Morinda citrifolia plant, and its chemical derivatives were identified to be active against major Gram-positive pathogens, particularly Streptococcus pneumoniae. Additional evidence indicated that 1a and its synthetic derivatives exerted their bactericidal activities against S. pneumoniae by selectively targeting the bacterial membrane, leading to the rapid lysis of the pneumococci. Efficient synthesis of 1a and its derivatives was performed using an application of the intramolecular aglycon delivery (IAD) reaction to establish its structure–activity relationships (SARs). SAR analysis indicated that trisaccharide glycolipid compounds showed good selectivity and high potency against S. pneumoniae. These compounds contain a linear chain with a chain length from C3 to C9 at the 2-position (R1) and 4′-position (R3), as well as a 2-methyl butyryl group at the 3′-position (R2), without an aza substitution in the lipid chain. This is the first lipotrisaccharide identified with potent bactericidal activity via interaction with cell membrane. The results reported herein offer a valuable guideline for the design of glycolipid derivatives that selectively target pathogenic bacteria.