Reversing the Trend: Deciphering Self-Assembly of Unconventional Amphiphiles Having Both Alkyl-Chain and PEG.

In the field of molecular self-assembly, the core of an assembly is always made up of hydrophobic moiety like a long alkyl chain, whereas the outer part has always been a hydrophilic moiety such as poly(ethylene glycol) (PEG), or charged species. Hence, reversing the trend to manifest self-assembled structures with a PEG core and a surface consisting of alkyl chains in aqueous system is incredibly challenging. Herein, we architected a unique class of cationic bolaamphiphiles containing low molecular weight PEG and alkyl chains of different lengths. The bolaamphiphiles spontaneously form vesicles without external stimuli. These vesicles are unprecedented because PEG makes up the vesicle core, while the alkyl chains appear on the vesicles' exterior. Hence, this particular design reverses the usual trend of self-assembly formation. The vesicle size increases with the increase in alkyl chain-length. To our great surprise, we obtained large micelles for longest alkyl-chain amphiphile, which in turn act as a gemini amphiphile. The shift from a particular bolaamphiphile to gemini amphiphile with the variation of alkyl chain is also unexplored. Therefore, this specific class of self-assembled structure would compound a new paradigm in molecular self-assembly and supramolecular chemistry.

C-4-Modified Isotetrones Prevent Biofilm Growth and Persister Cell Resuscitation in Mycobacterium smegmatis.

Hyperphosphorylated nucleotide (p)ppGpp, synthesized by Rel protein, regulates the stringent response pathway responsible for biofilm and persister cell growth in mycobacteria. The discovery of vitamin C as an inhibitor of Rel protein activities raises the prospect of tetrone lactones to prevent such pathways. The closely related isotetrone lactone derivatives are identified herein as inhibitors of the above processes in a mycobacterium. Synthesis and biochemical evaluations show that an isotetrone possessing phenyl substituent at C-4 inhibit the biofilm formation at 400 µg mL-1, 84 h post-exposure, followed by moderate inhibition by the isotetrone possessing the p-hydroxyphenyl substituent. The latter isotetrone inhibits the growth of persister cells at 400 µg mL-1 f.c. when monitored for 2 weeks, under PBS starvation. Isotetrones also potentiate the inhibition of antibiotic-tolerant regrowth of cells by ciprofloxacin (0.75 µg mL-1) and thus act as bioenhancers. Molecular dynamics studies show that isotetrone derivatives bind to the RelMsm protein more efficiently than vitamin C at a binding site possessing serine, threonine, lysine, and arginine.