The study found that a few antimicrobial peptides become much more powerful against E. coli when mixed with human blood plasma, thanks to the complement system, but this boost doesn’t happen for Staph infections or for peptides that work inside bacteria. This means the body’s own proteins can help certain antibiotics work better, though the effect isn’t seen with all bacteria or drug types.

Antimicrobial peptides (AMPs) are promising leads for novel antibiotics; however, their activity is often compromised under physiological conditions. The purpose of this study was to determine the activity of α-peptide/β-peptoid peptidomimetics and AMPs against Escherichia coli and Staphylococcus aureus in the presence of human blood-derived matrices and immune effectors. The minimum inhibitory concentration (MIC) of two peptidomimetics against E. coli decreased by up to one order of magnitude when determined in 50% blood plasma as compared to MHB media. The MIC of a membrane-active AMP, LL-I/3, also decreased, whereas two intracellularly acting AMPs were not potentiated by plasma. Blood serum had no effect on activity against E. coli and neither matrix had an effect on activity against S. aureus. Unexpectedly, physiological concentrations of human serum albumin did not influence activity. Plasma potentiation was not mediated by an LL-37 analogue, lysozyme or hydrogen peroxide; however, plasma potentiation of activity was abolished when the complement system was heat-inactivated. Time-course experiments indicated that potentiation was due to plasma-mediated effects on bacterial cells prior to activities of peptidomimetics. The unexpected enhancement of antibacterial activity of peptidomimetics and AMPs under physiological conditions significantly increases the therapeutic potential of these compounds.