期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 127, 期 -, 页码 223-234出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2016.12.060
关键词
Antibacterial agent; Methicillin resistant Staphylococcus aureus (MRSA); Mycobacterium smegmatis; Antibiotic resistance; Triazene
资金
- Ministry of Education, Science and Sport, Republic of Slovenia
- Slovenian Research Agency [P1-0230]
- Slovene Human Resources Development and Scholarship Found
- Research Cooperation of Doctoral Students Abroad [11012-5/2013, 11012-10/2014]
- Ministry of Science, Education and Sport of the Republic of Croatia [098-0982913-2748]
- Medical Research Council
- BBSRC UK
- BBSRC [BB/N003241/1, BB/M005011/1, BB/N00390X/1, BB/K017268/1] Funding Source: UKRI
- EPSRC [EP/M027503/1] Funding Source: UKRI
- MRC [G0500643, MR/N002679/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/N003241/1, BB/M005011/1, BB/N00390X/1, BB/K017268/1] Funding Source: researchfish
- Medical Research Council [MR/N002679/1, G0500643] Funding Source: researchfish
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 mu g/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(-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. Crown Copyright (C) 2016 Published by Elsevier Masson SAS. All rights reserved.
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