Vajs, Jure, Proud, Conor, Brozovic, Anamaria, Gazvoda, Martin, Lloyd, Adrian J., Roper, David I., Osmak, Maja, Košmrlj, Janez and Dowson, Christopher G. (2017) Diaryltriazenes as antibacterial agents against methicillin resistant Staphylococcus aureus (MRSA) and Mycobacterium smegmatis. European Journal of Medicinal Chemistry, 127 . pp. 223-234. doi:10.1016/j.ejmech.2016.12.060

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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.

Item Type:	Journal Article
Subjects:	Q Science > QR Microbiology R Medicine > RM Therapeutics. Pharmacology
Divisions:	Faculty of Science > Life Sciences (2010- )
Library of Congress Subject Headings (LCSH):	Drug resistance in microorganisms, Antibacterial agents , Staphylococcus aureus, Mycobacterium, Triazenes
Journal or Publication Title:	European Journal of Medicinal Chemistry
Publisher:	Elsevier Masson
ISSN:	0223-5234
Official Date:	15 February 2017
Dates:	Date Event 15 February 2017 Published 31 December 2016 Available 30 December 2016 Accepted 3 November 2016 Submitted
Date of first compliant deposit:	11 January 2017
Volume:	127
Page Range:	pp. 223-234
DOI:	10.1016/j.ejmech.2016.12.060
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	Slovenia. Ministrstvo za izobraževanje, znanost in šport (MIZŠ), Javna Agencija za Raziskovalno Dejavnost Republike Slovenije [Public Research Agency of the Republic of Slovenia] (ARRS), Javni Sklad Republike Slovenije za Razvoj Kadrov in Štipendije [Slovene Human Resources and Scholarship Fund], Croatia. Ministarstvo znanosti, obrazovanja i športa, Medical Research Council (Great Britain) (MRC), Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC)
Grant number:	Grant P1 - 0230 (ARRS), Grants 11012-5/2013 and 11012-10/2014 [Slovene Human Resources and Scholarship Fund], Project N o. 098 - 0982913 - 2748 (Croatia. Ministarstvo znanosti, obrazovanja i športa)
RIOXX Funder/Project Grant:	Project/Grant ID RIOXX Funder Name Funder ID UNSPECIFIED Slovenia. Ministrstvo za izobraževanje, znanost in šport (MIZŠ) UNSPECIFIED P1 - 0230 Javna Agencija za Raziskovalno Dejavnost Republike Slovenije [Public Research Agency of the Republic of Slovenia] (ARRS) UNSPECIFIED 11012-5/2013 Javni Sklad Republike Slovenije za Razvoj Kadrov in Štipendije [Slovene Human Resources and Scholarship Fund] UNSPECIFIED 11012-10/2014 Javni Sklad Republike Slovenije za Razvoj Kadrov in Štipendije [Slovene Human Resources and Scholarship Fund] UNSPECIFIED 098 - 0982913 - 2748 Croatia. Ministarstvo znanosti, obrazovanja i športa UNSPECIFIED UNSPECIFIED [MRC] Medical Research Council http://dx.doi.org/10.13039/501100000265 UNSPECIFIED [BBSRC] Biotechnology and Biological Sciences Research Council http://dx.doi.org/10.13039/501100000268

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