Structure-Activity Relationships And Action Mechanism Studies Of Cell-penetrating Peptide Transportan 10 And Its Analogues Against Drug-resistant Bacteria

Currently,antimicrobial resistance is an increasingly serious problem all over the world.The increased emergence of multidrug-resistant bacteria is perceived as a critical threat to human health,creating an urgent need for the development of novel classes of antimicrobials,which are safe and effective.Antimicrobial peptides(AMPs)could be developed into new antibacterial material due to character of broad-spectrum antimicrobial activity,special mechanism and not easy to produce bacterial resistance.Cell-penetrating peptides(CPPs)are a family of short peptides that have the ability to translocate a wide range of different bioactive molecules into living cells.AMPs and CPPs share some similar structure characteristics,such as cationic,amphiphilic and high affinity for membranes.CPPs have been found to have antimicrobial activity in many recent studies.More importantly,CPPs show higher cell selectivity and lower toxicity compared to AMPs and are currently being considered as potential alternatives to antibiotics.In this study,we designed a series of TP10 analogues based on our previous work and studied their structure-activity relationships and antimicrobial mechanism.First,we evaluated the antimicrobial activities of these compounds against multidrug-resistant bacteria,which are responsible for most nosocomial infections.Our results showed that some of these compounds had potent antimicrobial and biofilm-inhibiting activities.In the structure-activity relationships studies,we find that Lys substitution could increase both antimicrobial and antibiofilm activities but significantly enhanced the cytotoxicity.Pro introduction could reduce the cytotoxicity but disrupted the ?-helical structure,resulting in a decrease of activity.In the mechanism studies,Transportan 10 killed bacteria by membrane-active and DNA binding activities,which is quite different from some traditional antibiotics.In conclusion,Transportan 10 and its analogues could be developed into promising antibiotic candidates for the treatment of infections caused by multidrug-resistant bacteria.