Small molecule design strategy to overcome antibiotic resistance

Abstract Purpose Although antimicrobial peptides have been shown to avert resistance, most small molecule antibiotics do not share that characteristic. Antimicrobial peptides though are often less stable environmentally and have difficult delivery problems. However, small molecules are much easier to develop from a pharmaceutical perspective. This study has combined the properties of antimicrobial peptides into a small molecule platform. Methods Using our design platform which consists of microbiology, biophysical (including NMR), and animal data we have used the molecular backbone of a xanthone, alpha‐mangostin which is extracted from the pericarp of the SE Asian fruit, mangosteen. The xanthone is a heterocyclic planar molecule with sites at carbons 3 and 6 modifiable with amino acids or other functional groups. Stable, water soluble compounds have been developed whose activities are tested in vitro in microbiological assays as well as in mouse models of corneal infection. These molecules have been tested in MIC, time kill studies and in simulations of resistance. Results The results show that the antimicrobial activities of the cationic xanthone derivatives can be generally predicted based on the pKa values of the corresponding amines. We have identified AM‐0016 (3b) as the most potent compound in the series with potent antimicrobial activity with MIC values of 0.095‐0.39 (µg/mL) against Gram‐positive bacteria including MRSA, improved selectivity up to 200, rapid time‐kill in 10‐30mins, Conclusion A series of novel antimicrobials have been designed and prepared by cationic modifications of α‐mangostin, a natural xanthones with a planar hydrophobic core, to yield an amphiphilic structure which improves selectivity for bacterial membranes through the hydrophobic‐water interface perturbation.