title: Diaryltriazenes as antibacterial agents against methicillin resistant Staphylococcus aureus (MRSA) and Mycobacterium smegmatis.
abstract: 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.
authors.affiliation: Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, SI-1000, Ljubljana, Slovenia.
authors.forename: Jure
authors.initials: J
authors.lastname: Vajs
authors.affiliation: School of Life Sciences, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, United Kingdom.
authors.forename: Conor
authors.initials: C
authors.lastname: Proud
authors.affiliation: Division of Molecular Biology, Ruđer Bošković Institute, Bijenička cesta 54, HR-10000, Zagreb, Croatia.
authors.forename: Anamaria
authors.initials: A
authors.lastname: Brozovic
authors.affiliation: Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, SI-1000, Ljubljana, Slovenia.
authors.forename: Martin
authors.initials: M
authors.lastname: Gazvoda
authors.affiliation: School of Life Sciences, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, United Kingdom.
authors.forename: Adrian
authors.initials: A
authors.lastname: Lloyd
authors.affiliation: School of Life Sciences, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, United Kingdom.
authors.forename: David I
authors.initials: DI
authors.lastname: Roper
authors.affiliation: Division of Molecular Biology, Ruđer Bošković Institute, Bijenička cesta 54, HR-10000, Zagreb, Croatia. Electronic address: Maja.Osmak@irb.hr.
authors.forename: Maja
authors.initials: M
authors.lastname: Osmak
authors.affiliation: Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, SI-1000, Ljubljana, Slovenia. Electronic address: janez.kosmrlj@fkkt.uni-lj.si.
authors.forename: Janez
authors.initials: J
authors.lastname: Košmrlj
authors.affiliation: School of Life Sciences, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, United Kingdom. Electronic address: C.G.Dowson@warwick.ac.uk.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Dowson
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D020102:Mycobacterium smegmatis / Q000187:drug effects*; D014226:Triazenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D000900:Anti-Bacterial Agents; D014226:Triazenes
keywords: Antibacterial agent; Antibiotic resistance; Methicillin resistant Staphylococcus aureus (MRSA); Mycobacterium smegmatis; Triazene