Abstract
Antimicrobial peptides (AMPs) have emerged as a promising alternative to small molecule antibiotics. Although AMPs have previously been isolated in many organisms, efforts on the systematic identification of AMPs in fish have been lagging. Here, we collected peptides from the plasma of medaka (Oryzias latipes) fish. By using mass spectrometry, 6399 unique sequences were identified from the isolated peptides, among which 430 peptides were bioinformatically predicted to be potential AMPs. One of them, a thermostable 13-residue peptide named BING, shows a broad-spectrum toxicity against pathogenic bacteria including drug-resistant strains, at concentrations that presented relatively low toxicity to mammalian cell lines and medaka. Proteomic analysis indicated that BING treatment induced a deregulation of periplasmic peptidyl-prolyl isomerases in gram-negative bacteria. We observed that BING reduced the RNA level of cpxR, an upstream regulator of envelope stress responses. cpxR is known to play a crucial role in the development of antimicrobial resistance, including the regulation of genes involved in drug efflux. BING downregulated the expression of efflux pump components mexB, mexY and oprM in P. aeruginosa and significantly synergised the toxicity of antibiotics towards these bacteria. In addition, exposure to sublethal doses of BING delayed the development of antibiotic resistance. To our knowledge, BING is the first AMP shown to suppress cpxR expression in Gram-negative bacteria. This discovery highlights the cpxR pathway as a potential antimicrobial target.
Highlights
Antimicrobial peptides (AMPs) have emerged as a promising alternative to small molecule antibiotics
AMPs have been identified in circulating c ells[21,22], blood plasma has rarely been used as a resource for AMP discovery: only five AMPs have been identified in plasma so far[23,24]
While the general antibacterial mechanisms of cationic amphipathic peptides have been extensively d escribed[3], some AMPs have been shown to bind to non-canonical molecular targets[26,27], suggesting that the range of antibacterial mechanisms utilized by AMPs is not fully understood
Summary
Antimicrobial peptides (AMPs) have emerged as a promising alternative to small molecule antibiotics. A recently published “roadmap for antibiotic development”[7] recommended the identification and optimization of natural products with antibacterial activities, especially against Gram-negative organisms. It calls for more research on combinational therapies by exploring the potential synergistic effects of antibacterial agents. Recent findings have indicated that antibiotic-resistant bacteria are generally collaterally sensitive to a wide range of AMPs8 and that AMPs are less likely to induce resistance[9,10]. These characteristics make AMPs a promising candidate in combinatory anti-bacterial therapies[11]. Due to the lack of mechanistic understanding of AMP functions, the rational design of combined therapies, either with other A MPs28 or small-molecule antibiotics[29], is still not comprehensive
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