Functionalized Phenyl Peptoids with Enhanced Antibacterial Potency

Antimicrobial resistance (AMR) to traditional antibiotics and natural peptides has been recognized as a global challenge requiring efforts to address its widespread impact. Peptoids represent a promising class of peptidomimetics with proven activity against multidrug-resistant bacteria and show less susceptibility to enzymatic degradation. In this study, building on our previous design of dimeric peptoids, 22 amino and guanidino compounds of functionalized phenyl-dimeric peptoids were synthesized, incorporating electron-withdrawing and donating substituents, as well as the parent peptoid without substituents. The electronic nature of the substituent and the guanidino group played a vital role in tuning the peptoid antibacterial activity. Guanidino peptoids <b>11h</b>, <b>11i</b>, and <b>11f</b> were the most effective peptoids against Gram-positive and Gram-negative bacteria, with MICs of 0.75 to 2.6 μg mL^-1 against <i>Staphylococcus aureus</i> strains and MICs of 6 to 10.9 μg mL^-1 against <i>Escherichia coli</i>. Guanidino peptoids in the presence of the electron-withdrawing group, including halogens and a nitro group, or in the presence of moderate electron-donating groups such as methyl and <i>tert</i>-butyl, showed the best activity against bacteria, especially Gram-positive strains. Mechanistic studies using cytoplasmic membrane permeability and flow cytometric viability measurements revealed that the antibacterial effect might be mostly attributed to bacterial cell membrane damage. These promising antibacterial peptoids exhibited negligible hemolysis of mammalian red blood cells. Peptoid <b>11f</b>, containing a methyl group, was the most effective disruptor and inhibitor of <i>S. aureus</i> or <i>E. coli</i> biofilms. These peptoids have the potential to be used as antibacterial surface coatings or therapeutic antibacterial agents.