AUTHOR=Rodríguez-Rojas Alexandro , Nath Arpita , El Shazely Baydaa , Santi Greta , Kim Joshua Jay , Weise Christoph , Kuropka Benno , Rolff Jens 

TITLE=Antimicrobial Peptide Induced-Stress Renders Staphylococcus aureus Susceptible to Toxic Nucleoside Analogs

JOURNAL=Frontiers in Immunology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.01686

DOI=10.3389/fimmu.2020.01686

ISSN=1664-3224

ABSTRACT=<p>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 <italic>Staphylococcus aureus</italic> at sub-lethal concentrations using quantitative proteomics. Several proteins involved in nucleotide metabolism were elevated, suggesting a metabolic demand. We then show that <italic>Staphylococcus aureus</italic> 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.</p>