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.
Highlights
The emergence of multidrug-resistant pathogens emphasizes the need for novel and alternative therapeutics to fight against infections (Marston et al, 2016)
The antibacterial activities of S1, S1-Nal, S1-Nal-Nal, vancomycin, ciprofloxacin, and tetracycline against Grampositive bacterium including vancomycin-resistant E. faecium BCRC 15B0132 (VRE) and Gram-negative bacteria including A. baumannii BCRC 14B0091, A. baumannii BCRC 14B0097, A. baumannii BCRC 14B0100, E. coli BCRC 13B0198, and E. coli BCRC 13B0207 were assessed by minimal inhibitory concentrations (MICs) assay
These results indicated that the addition of only one or two bulky non-natural amino acid end tags could boost the antimicrobial activity
Summary
The emergence of multidrug-resistant pathogens emphasizes the need for novel and alternative therapeutics to fight against infections (Marston et al, 2016). Some AMPs can work synergistically with conventional antibiotics to overcome the resistant problems and reduce the amount of antibiotics (Cassone and Otvos, 2010; Sierra et al, 2017; Martinez et al, 2019; Zharkova et al, 2019; Li et al, 2020). Tryptophan, owing to its membrane disruptive and lipid interface anchoring activities, has been found to play important roles in the design and development of Trp-rich AMPs (Mojsoska and Jenssen, 2015; Godballe et al, 2016; Arias et al, 2018). A Trp-rich peptide PEM2-W5K/A9W (Ac-KKWRKWLKWLAKK-NH2) was developed based on the C-terminal region of Bothrops asper myotoxin II (Yu et al, 2010).
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