Antibiotic resistance poses a critical threat to global health care. Alkyl-and aryltriazene compounds have found utility as DNA-modifying agents and have been previously 2 assessed as potential anti-cancer therapeutics. However, their potential utility as antimicrobials has only recently been appreciated. Therefore, to further investigate the efficacy of these compounds as antibiotics, we synthesized a series of forty six diaryltriazene derivatives and evaluated their antimicrobial properties. Initial experiments showed activity of some diaryltriazene compounds against both methicillin-resistant strains of Staphylococus aureus (MRSA) and against Mycobacterium smegmatis with MICs of less than 0.02 and 1 μg/mL. Those diaryltriazene compounds with potent anti-staphylococcal and anti-mycobacterial activity were inactive as growth inhibitors of mammalian cell lines and yeast. Furthermore, we demonstrated that one of the most active anti-MRSA diaryltriazene derivatives was subject to very low frequencies of resistance at < 10 -9 . Whole genome sequencing of resistant isolates identified mutations in the enzyme that lysylates phospholipids. This could result in the modification of phospholipid metabolism and consequently the characteristics of the staphylococcal cell membrane, ultimately modifying the sensitivity of these pathogens to triazene challenge. Our work has therefore extended the potential range of triazenes, which could yield novel antimicrobials with low levels of resistance.
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