Phenol‐Soluble‐Modulin‐Inspired Amphipathic Peptides Have Bactericidal Activity against Multidrug‐Resistant Bacteria

Abstract

Phenol‐soluble modulins (PSMs) are a large family of cytolytic peptide toxins produced by Staphylococcus aureus. Based on their amino acid sequences, we have constructed a small library of cationic isoleucine‐rich peptides for antimicrobial evaluation. Relative to the parent PSMs, peptide zp3 (GIIAGIIIKIKK‐NH2) was found to possess greatly improved physicochemical properties (soluble in water) and antibacterial activity (MIC=8 μm for E. coli, B. subtilis, and C. freundii) while maintaining low hemolytic activity (<5 % at 256 μm) and cytotoxicity (HEK293 cells IC50>80 μm). We reasoned that the selective activity of zp3 toward bacterial cells is due to its amphiphilic nature and positive net charge. Moreover, it is difficult for bacteria to develop resistance against zp3. Through microscopic studies of E. coli, we demonstrated that zp3 can penetrate the bacterial membrane, thereby causing leakage of the bacterial cytoplasm. Our findings present a promising antimicrobial peptide lead, which has great potential for further chemical modification.

Antimicrobials from a feline commensal bacterium inhibit skin infection by drug-resistantS. pseudintermedius

“…Alternatively, small α-helical AMPs, which include mammalian cathelicidin (active and defensins (Nakatsuji and Gallo, 2012) as well as bacterial PSMs (Cogen et al, 2010;Zeng et al, 2019), could be better candidates.…”

“…Furthermore, they are difficult to purify and synthesize, and are unstable and sensitive to proteases, pH, and oxidation (Ross and Vederas, 2011). Alternatively, small α-helical AMPs, which include mammalian cathelicidin (active LL-37) and defensins (Nakatsuji and Gallo, 2012) as well as bacterial PSMs (Cogen et al, 2010; Zeng et al, 2019), could be better candidates.…”

“…The concomitant accumulation of bacterial ROS and decrease in ATP production are also consistent with bacterial membrane disruption and increased permeability (Song et al, 2020). Future research efforts will attempt to develop and characterize truncated and mutated versions of S. felis PSMs with the goal of enhancing antimicrobial activity for a more simplistic but potentially more powerful therapeutic (Zeng et al, 2019).…”

Supramolecular Peptide Assemblies as Antimicrobial Scaffolds

“…These assembly domains on their own did not show functional antimicrobial activity, supporting the assertion that fibrillization itself does not confer activity but rather enhances the bacteriolytic effects and specificity of antimicrobial motifs. Other antimicrobial sequences derived from the PSM family of peptides have also been recently engineered to combat MDR bacteria [ 94 ]. The lead candidate peptide zp3 (GIIAGIIIKIKK-NH 2 ) displayed an MIC of 8 μM toward E. coli , B. subtilis , and C. freundii , and generated minimal hemolytic activity (<5% at 256 μM) and cytotoxicity toward HEK293 cells (IC 50 > 80 μM) when employed well above its microbicidal concentration.…”

Faculty Opinions recommendation of Supramolecular peptide assemblies as antimicrobial scaffolds.

“…These assembly domains on their own did not show functional antimicrobial activity, supporting the assertion that fibrillization itself does not confer activity but rather enhances the bacteriolytic effects and specificity of antimicrobial motifs. Other antimicrobial sequences derived from the PSM family of peptides have also been recently engineered to combat MDR bacteria [94]. The lead candidate peptide zp3 (GIIAGIIIKIKK-NH 2 ) displayed an MIC of 8 µM toward E. coli, B. subtilis, and C. freundii, and generated minimal hemolytic activity (<5% at 256 µM) and cytotoxicity toward HEK293 cells (IC 50 > 80 µM) when employed well above its microbicidal concentration.…”