Abstract
Cationic antimicrobial peptides (AMPs) are active immune effectors of multicellular organisms and are also considered as new antimicrobial drug candidates. One of the problems encountered when developing AMPs as drugs is the difficulty of reaching sufficient killing concentrations under physiological conditions. Here, using pexiganan, a cationic peptide derived from a host defense peptide of the African clawed frog and the first AMP developed into an antibacterial drug, we studied whether sub-lethal effects of AMPs can be harnessed to devise treatment combinations. We studied the pexiganan stress response of Staphylococcus aureus at sub-lethal concentrations using quantitative proteomics. Several proteins involved in nucleotide metabolism were elevated, suggesting a metabolic demand. We then show that Staphylococcus aureus is highly susceptible to antimetabolite nucleoside analogs when exposed to pexiganan, even at sub-inhibitory concentrations. These findings could be used to enhance pexiganan potency while decreasing the risk of resistance emergence, and our findings can likely be extended to other antimicrobial peptides.
Highlights
Antimicrobial peptides (AMPs, we use antimicrobial peptides (AMPs) here as synonymous with host defense peptides) are immune effector molecules used by multicellular organisms to control infections [1,2,3]
We examined S. aureus exposed to pexiganan by studying proteome-wide changes after a 30-min treatment with different pexiganan concentrations (0.125, 0.25, 0.5, and 1x minimum inhibitory concentration (MIC), Table S1)
We have found that pexiganan, a cationic antimicrobial peptide, can induce a stress response in S. aureus that results in a proteome-wide impact
Summary
Antimicrobial peptides (AMPs, we use AMPs here as synonymous with host defense peptides) are immune effector molecules used by multicellular organisms to control infections [1,2,3] These peptides are usually active against a broad spectrum of bacterial pathogens and some display activity against antibiotic-resistant bacteria. One common problem with the development of AMPs as drugs is that, under physiological conditions, their antimicrobial activity cannot be recaptured and the required dosage is extremely high [15] This dosage issue can be addressed by making use of synergistic combinations of AMPs [16], a property common in natural defense cocktails [17, 18]
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