Development of a Potent Antimicrobial Peptide With Photodynamic Activity

Abstract

The emergence of antibiotic-resistant bacteria poses a serious challenge to medical practice worldwide. A small peptide with sequence RWRWRW was previously identified as a core antimicrobial peptide with limited antimicrobial spectrum to bacteria, especially Gram-positive bacteria. By conjugating this peptide and its analogs with lipophilic phthalocyanine (Pc), we identified a new antibiotic peptide [PcG3K5(RW)3]. The peptide demonstrates increased antimicrobial effect to both Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli. In addition, Pc also provides added and potent antimicrobial effect upon red light illumination. The inhibitory efficacy of PcG3K5(RW)3 was increased by ~140-fold to nanomolar range upon illumination. Moreover, PcG3K5(RW)3 was safe for mammalian cell and promoted wound healing in the mouse infection model. Our work provides a new direction to optimize antimicrobial peptides to enhance antimicrobial efficacy.

Secondary Structure Stabilization of Macrocyclic Antimicrobial Peptides via Cross-Link Swapping

“…Antibacterial activities of lactams 2 – 5 and R2 – R5 were compared to those of disulfides 1 and R1 and ampicillin as positive control in tests against both Gram-(+) and -(−) pathogenic strains (Figure S31, Figure S32 and Table ). Bacterial cell viability curves were typically nonlinear, which is characteristic of many AMPs. − Lactams containing Dab residues ( 3 and 5 ) as well as their inverse analogues ( R3 and R5 ) all exhibited significantly improved antibacterial activities compared to disulfide ( 1 and R1 ) and Dap lactams ( 2 , 4 , R2 , and R4 ). Against Staphylococcus epidermidis, Dab analogues ( 3 , R3 , 5 , and R5 ) exhibited lower minimal inhibitory concentration (MIC) values than ampicillin.…”

Synthesis of Photosensitizers Based on Tetrapyrrolic Macrocycles for Combination with Antibiotics: Dual Inactivation of Bacteria

“…Recently, Huang [78] reported a phthalocyanine covalently coupled with the antibiotic RWRWRW‐peptide ( PS15 ). The β‐carboxy‐phthalocyanine 39 was obtained using a two‐step methodology (Scheme 17), [79] in which trimellitic anhydride 36 and an excess of phthalic anhydride 37 , were mixed in the presence of Zn(OAC) 2 , urea, ammonium molybdate and ammonium chloride, at 170 °C with stirring for 4 h. After cooling to room temperature, the reaction crude was washed with HCl and water, obtaining 38 in 67 %, estimated by HPLC.…”

“…The conjugation of the lipophilic Zn phthalocyanine with a cationic antimicrobial peptide PS15 boosted the antibacterial activity of this AB against both S. aureus and E. coli , achieving 6 and 3 log CFU reductions, respectively, using 8 μM conjugate and 12 J/cm 2 light dose. Moreover, it exhibited low toxicity towards mammalian cell and promoted wound healing in a mouse infection model (entry 7) [78] …”

“…Moreover, it exhibited low toxicity towards mammalian cell and promoted wound healing in a mouse infection model (entry 7). [78] Regarding chlorin e6 + AB covalent combinations, the chlorin-e6 conjugate with the antimicrobial peptide TAT PS16 was used in combination with tinidazole for the inactivation of P. gengivalis, which improved its in vitro activity by 2-fold, when compared with PDI using the conjugate only. Further in vivo studies in mice with periodontitis gave a better therapeutic outcome regarding the preservation of epithelial cells and management of inflammation (entry 8).…”

Potential Broad-Spectrum Antimicrobial, Wound Healing, and Disinfectant Cationic Peptide Crafted from Snake Venom

“…For SP1V3_1, the MIC values were similar and, in some instances, lesser than previously reported studies on AMPs. 25,26 The MBCs of SP1V3_1 for the respective organisms were found to be 4.5, 8, 6, and 11 μM (Figure S20). It must be noted that the MICs of the FLPII deletion analog of SP1V3_1, SP1V3_1_D, were observed to be >100 μM for all the tested organisms, signifying minimum antibacterial efficiency.…”