Vajs Jure, Proud Conor, Brozovic Anamaria, Gazvoda Martin, Lloyd Adrian, Roper David I, Osmak Maja, Košmrlj Janez, Dowson Christopher G
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, SI-1000, Ljubljana, Slovenia.
School of Life Sciences, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, United Kingdom.
Eur J Med Chem. 2017 Feb 15;127:223-234. doi: 10.1016/j.ejmech.2016.12.060. Epub 2016 Dec 31.
Diaryltriazene derivatives were synthesized and evaluated for their antimicrobial properties. Initial experiments showed some of these compounds to have activity against both methicillin-resistant strains of Staphylococus aureus (MRSA) and Mycobacterium smegmatis, with MICs of 0.02 and 0.03 μg/mL respectively. Those compounds with potent anti-staphylococcal and anti-mycobacterial activity were not found to act as growth inhibitors of mammalian cell lines or yeast. Furthermore, we demonstrated that one of the most active anti-MRSA diaryltriazene derivatives was subject to very low frequencies of resistance at <10. 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.
合成了二芳基三氮烯衍生物并对其抗菌性能进行了评估。初步实验表明，其中一些化合物对耐甲氧西林金黄色葡萄球菌（MRSA）和耻垢分枝杆菌均有活性，最低抑菌浓度分别为0.02和0.03μg/mL。未发现具有强效抗葡萄球菌和抗分枝杆菌活性的那些化合物对哺乳动物细胞系或酵母有生长抑制作用。此外，我们证明，活性最强的抗MRSA二芳基三氮烯衍生物之一产生耐药性的频率极低，低于10。对耐药菌株进行全基因组测序，确定了磷脂赖氨酰化酶发生了突变。这可能导致磷脂代谢发生改变，进而改变葡萄球菌细胞膜的特性，最终改变这些病原体对三氮烯攻击的敏感性。因此，我们的工作扩展了三氮烯的潜在应用范围，有望产生耐药性低的新型抗菌药物。
