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

Abstract

Antibiotic resistance poses a critical threat to global health care. Alkyl-and aryltriazene compounds have found utility as DNA-modifying agents and have been previously 2 assessed as potential anti-cancer therapeutics. However, their potential utility as antimicrobials has only recently been appreciated. Therefore, to further investigate the efficacy of these compounds as antibiotics, we synthesized a series of forty six diaryltriazene derivatives and evaluated their antimicrobial properties. Initial experiments showed activity of some diaryltriazene compounds against both methicillin-resistant strains of Staphylococus aureus (MRSA) and against Mycobacterium smegmatis with MICs of less than 0.02 and 1 μg/mL. Those diaryltriazene compounds with potent anti-staphylococcal and anti-mycobacterial activity were inactive as growth inhibitors of mammalian cell lines and 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.

Assessment of the biological potential of diaryltriazene-derived triazene compounds

“…Conversely, the C1-N11 15)°] 66 . The diazoamino moiety of 1,3-disubstituted triazenes and strategically substituted terminal aryl substituents provide intermolecular interactions through hydrogen bonds, with polarizable and electronegative acceptor atoms of the terminal substituents 31,34 , giving rise to supramolecular arrays. The current study of intermolecular hydrogen bond interactions in solid-state symmetrically disubstituted 1,3-diaryltriazenes shows the crystal structure of compound 1 (Fig.…”

“…New diaryltriazene-derived compounds have been synthesized, and their antimicrobial properties have also been evaluated 34 . Previously 19 , the antimicrobial activities of diaryltriazenes, including antifungal activity of novel hydroxytriazenes (Candida albicans, Cryptococcus neoformans, Sporotrichum schenckii, Trichophyton mantagrophytes, and Aspergillus fumigatus) 20 , anorexics, and anticancer activity 34 have been explored. In these studies, the alkyltriazenes' mechanism of action was generally linked to the formation of reactive diazonium species capable of DNA alkylation 12 .…”

“…This evidence has had a major impact because these mechanisms of bacterial resistance are among the most prevalent. Several triazenes with potential antimicrobial activity against MRSA and M. Smegmatis have been identified 34 .…”

Microbiological and molecular insights on rare Actinobacteria harboring bioactive prospective

“…The emergence and spread of multi-resistant pathogens became near to all known antibiotics (Yong et al, 2009), which cause the urgent need for searching for new antibiotics. The emergence of multidrug resistance among bacteria including Staphylococcus aureus, members of the ESKAPE pathogens, and latterly extreme drug-resistant Mycobacterium tuberculosis is a major worldwide public health threat (Pfaller et al, 1998;Vajs et al, 2017). It has been reported that numerous bioactive compounds were isolated from Actinobacteria and inhibited multidrug-resistant pathogens such as vancomycin-resistant Enterococci, methicillinresistant Staphylococcus aureus, Shigella dysenteriae, Klebsiella sp., Escherichia coli, and Pseudomonas aeruginosa (Selvameenal et al, 2009;Severin et al, 2014).…”

Synthesis and in vitro investigation of halogenated 1,3‐bis(4‐nitrophenyl)triazenide salts as antitubercular compounds

“…However, when classified as extensively drug-resistant tuberculosis (XDR) TB, the MDR M. tuberculosis strain has acquired additional resistance to one or more of the second-line drugs. [4] In addition, Vajs et al [10] reported on the nitroaromatic triazenes as efficient antimicrobials with low levels of resistance ( Figure 1b). One strategy to identify new antitubercular drug candidates that have gained popularity in the past decade is the repurposing of existing pharmacophores.…”