Diaryltriazenes as antibacterial agents against methicillin resistant Staphylococcus aureus (MRSA) and Mycobacterium smegmatis

• Published in: European journal of medicinal chemistry Vol. 127; pp. 223 - 234
• Main Authors: Vajs, Jure, Proud, Conor, Brozovic, Anamaria, Gazvoda, Martin, Lloyd, Adrian, Roper, David I., Osmak, Maja, Košmrlj, Janez, Dowson, Christopher G.
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 15.02.2017; Elsevier
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - toxicity; Antibacterial agent; Antibiotic resistance; Chemistry, Medicinal; Humans; Life Sciences & Biomedicine; Methicillin resistant Staphylococcus aureus (MRSA); Methicillin-Resistant Staphylococcus aureus - drug effects; Microbial Sensitivity Tests; Mycobacterium smegmatis; Mycobacterium smegmatis - drug effects; Pharmacology & Pharmacy; Science & Technology; Triazene; Triazenes - chemical synthesis; Triazenes - chemistry; Triazenes - pharmacology; Triazenes - toxicity; Mycobacterium smegmatis; Methicillin resistant Staphylococcus aureus (MRSA); Antibacterial agent; Triazene; Antibiotic resistance; SEQUENCE-ANALYSIS; MPRF; GENE; MECHANISM; 1,3-DIARYLTRIAZENES; REVEALS
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2016.12.060

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 <10−9. 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. [Display omitted] •New triazenes with antimicrobial properties are synthesized.•High activity against MRSA (0.02 μg/mL) and M. Smegmatis (0.03 μg/mL) is shown.•Compounds are not acting as growth inhibitors of mammalian cell lines or yeast.•Selected triazene is subject to very low frequencies of resistance at <10−9.•Whole genome sequencing of resistant isolates is performed.