The rapid emergence of bacterial strains that are resistant to most commercially available antibiotics is of great concern. This phenomenon has necessitated the urgent need for novel antibiotics to combat the resistant microbial strains. Natural antimicrobial peptides (AMPs) appear as a great source of inspiration in creating the newer generation of antibiotics due to their broad spectrum activities and low susceptibility to resistance development. We have recently reported the development of novel cyclic lipopeptides and its linear isomers that were inspired by amphiphilic features of AMPs. The lipopeptides constructs were built-up based on lysine and C12 lipoamino acids (LAAs) (D,L-2-amino-dodecanoic acid) as constituents. The synthesized lipopeptides were able to self-assemble into nanoparticles in an aqueous environment, with three exhibiting antibacterial activity against the multidrug-resistant Gram-positive bacteria species, including clinically isolate vancomycin resistant strains of S. aureus. TEM images revealed that the bacterial cell seemed to burst and showing open holes upon treatment with lipopeptides. Their remarkable potential as antibacterial agents was further enhanced by having a good safety profile, non-haemolytic and reasonable toxicity against the tested human cell lines.