Antibioticresistance is a critical global health care crisis requiringurgent action to develop more effective antibiotics. Utilizing thehydrophobic scaffold of xanthone, we identified three components thatmimicked the action of an antimicrobial cationic peptide to producemembrane-targeting antimicrobials. Compounds 5cand 6, which contain a hydrophobic xanthone core, lipophilic chains,and cationic amino acids, displayed very promising antimicrobial activityagainst multidrug-resistant Gram-positive bacteria, including MRSAand VRE, rapid time–kill, avoidance of antibiotic resistance,and low toxicity. The bacterial membrane selectivity of these moleculeswas comparable to that of several membrane-targeting antibiotics inclinical trials. 5cand 6were effectivein a mouse model of corneal infection by S. aureusand MRSA. Evidence is presented indicating that 5cand 6target the negatively charged bacterial membrane via a combinationof electrostatic and hydrophobic interactions. These results suggestthat 5cand 6have significant promise forcombating life-threatening infections. [ABSTRACT FROM AUTHOR]