Boosting Synergistic Effects of Short Antimicrobial Peptides With Conventional Antibiotics Against Resistant Bacteria

Abstract

The global spread of antibiotic-resistant infections has meant that there is an urgent need to develop new antimicrobial alternatives. In this study, we developed a strategy to boost and/or synergize the activity of conventional antibiotics by combination with antimicrobial peptides tagged with the bulky non-natural amino acid β-naphthylalanine (Nal) to their N- or C-terminus. A checkerboard method was used to evaluate synergistic effects of the parent peptide and the Nal-tagged peptides. Moreover, boron-dipyrro-methene labeled vancomycin was used to characterize the synergistic mechanism of action between the peptides and vancomycin on the bacterial strains. These Nal-tagged antimicrobial peptides also reduced the antibiotic-induced release of lipopolysaccharide from Gram-negative bacteria by more than 99.95%. Our results demonstrate that Nal-tagged peptides could help in developing antimicrobial peptides that not only have enhanced antibacterial activities but also increase the synergistic effects with conventional antibiotics against antibiotic-resistant bacteria.

Hibifolin, a Natural Sortase A Inhibitor, Attenuates the Pathogenicity of Staphylococcus aureus and Enhances the Antibacterial Activity of Cefotaxime

“…The checkerboard microtiter assay ( 38 ) was applied for determining the interaction of combinations of hibifolin with Cefotaxime, Doxycycline, Ceftriaxone Sodium, Vancomycin, Oxacillin sodium, Ceftiofur Sodium, Cefepime, Ceftaroline fosamil, relatively. One hundred microliters of CAMHB medium were added to a 96-well plate, followed by a fold dilution of hibifolin and antibiotics.…”

Synergy by Perturbing the Gram-Negative Outer Membrane: Opening the Door for Gram-Positive Specific Antibiotics

“… 179 , 180 Attempts at further improving the S1 peptide involved the introduction of Nal residues at the C-terminus to generate S1-Nal, which exhibited enhanced synergistic activity, and S1-Nal-Nal, which also exhibited enhanced synergistic activity but at the expense of increased hemolytic activity ( Table 3 ). 181 − 184 …”

“…Studies with peptide sequences based on the C-terminus of myotoxin II resulted in peptide S1 (Table ), which showed a good balance of synergy with vancomycin and low hemolytic activity. , Attempts at further improving the S1 peptide involved the introduction of Nal residues at the C-terminus to generate S1-Nal, which exhibited enhanced synergistic activity, and S1-Nal-Nal, which also exhibited enhanced synergistic activity but at the expense of increased hemolytic activity (Table ). − …”

Design and Evaluation of Short Bovine Lactoferrin-Derived Antimicrobial Peptides against Multidrug-Resistant Enterococcus faecium

“…Factors such as the presence of salts may compromise the antimicrobial potency of AMPs, including beta-defensin-1, clavanins, and gramicidin S [ 17 , 18 ]. Recently, several broad-spectrum AMPs, including SLAY-P1 (discovered through surface-localized antimicrobial display cationic peptides) [ 19 ], Bip-P-113 (that consists of bulky non-nature amino acids) [ 20 ], and BmKn2 (derived from scorpion) [ 21 ], demonstrated excellent antimicrobial activity against E. faecium . However, few studies investigate the rational development of narrow-spectrum AMPs specific to MDR E. faecium and there is no AMP currently in the clinical trial pipeline for development as a drug [ 22 ].…”