Design And Synthesis Of Novel Alpha-mangostin Based Antimicrobial Agent: A Synthetic Mimic Of Antimicrobial Peptides

The worldwide rapid development of bacterial resistance to conventional antibiotics is oneof the most imperative global healthcare issues today, leading to surgical treatment failure,increased complications, recurrent infection, prolonged hospitalization, increased use ofexpensive antibiotics and other drugs. Therefore, the search for novel antibiotics with newbiological targets is of great importance for the therapy of multidrug-resistant bacteriainfections. Synthetic membrane-targeted antibiotic, which mimics of the naturally occurringantimicrobial peptides (AMPs), is a new approach to develop new potential antibioticsemerging in these years.Alpha-mangostin is a tetraoxygenated diprenylated xanthone from the pericarp ofGarcinia mangostana. Alpha-mangostin showed excellent biological properties such asantibacterial, antifungal, antioxidant and antiviral. However, the toxicity is a barrier to impedethe use of alpha-mangostin as therapeutic agent. In our strategy, By engineering the twocationic groups into the hydrophobic alpha-mangostin scaffold, a series of new amphiphilicmolecules were synthesized to mimic AMPs.First, We designed and synthesized alpha-mangostin derivatives3a-3f.Our resultsdemonstrated that alpha-mangostin derivatives3a-3f showed excellent antimicrobial activityagainst Gram-positive bacteria and moderate antimicrobial activity against Gram-negativebacteria. Hemolysis assay showed that this series of alpha-mangostin derivatives redeuced thehemolytic concentration of alpha-mangostin.3-log reduction compound3b, one of the bestantibacterial compound, can be achieved rapidly in20minutes. In addition, multistep (20passage) resistance selection studies have shown that development of resistance against3bwas not observed.By modifying the natural alpha-mangostin, the synthesized mangositin derivativescaptured the structural and biological properties of both alpha-mangostin and AMPs. Thesecompounds are a kind of novel hydrid antimicrobial agent.