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© ConspectusAntibiotic resistance (AMR) is an increasing public health crisis worldwide. This threatens our ability to adequately care for patients with infections due to multi–drug–resistant (MDR) pathogens. As such, there is an urgent need to develop new classes of antimicrobials that are not based on currently utilized antibiotic scaffolds. One promising avenue of antimicrobial research that deserves renewed examination involves the use of peptides. Although antimicrobial peptides (AMPs) have been studied for a number of years, innovations in peptide design and their applications are increasingly making this approach a viable alternative to traditional small–molecule antibiotics. This review will provide updates on two ways in which peptides are being explored as antibiotics. The first topic will focus on novel types of peptides and conjugation methods that are being exploited to act as antibiotics themselves. These direct–acting modified peptides could serve as potentially useful drugs while mitigating many of the known liabilities of AMPs. The second topic relates to the use of peptides as delivery vehicles for other active compounds with antimicrobial activity. Cell–penetrating peptides (CPPs) are peptides designed to carry compounds across cell membranes and are a promising method for delivering a variety of antimicrobial compounds. When conjugated to other compounds, CPPs have been shown to be effective at increasing the uptake of both small– and large–molecular–weight compounds. This includes conjugation to antisense molecules and traditional antibiotics, resulting in increased effectiveness of these antimicrobials. One particular approach utilizes CPPs conjugated to phosphorodiamidate morpholino oligomers (PMOs). PMOs are designed to target particular pathogens in a gene–specific way. They target mRNA and block protein translation. Peptide–conjugated PMOs (PPMOs) allow for efficient delivery into the Gram–negative cytoplasm, and recent updates to their in vitro and in vivo activity are reviewed. This includes recent data to suggest that PPMOs maintain activity in the setting of multi–drug–resistant (MDR) strains, an important finding as it relates to the further development of this therapeutic approach. Other topics include the ability to have activity in the biofilm setting, a finding that likely relates to the peptide portion of the conjugate. Finally, what is known and anticipated related to the development of resistance to these peptides will be discussed.
