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Cultures of the emerging cystic fibrosis pathogen <jats:italic>Mycobacteroides\u00a0abscessus<\/jats:italic> detoxify HQNO by methylating the <jats:italic>N<\/jats:italic>\u2010hydroxy moiety. In this study, the class I methyltransferase MAB_2834c and its orthologue from <jats:italic>Mycobacterium\u00a0tuberculosis<\/jats:italic>, Rv0560c, were identified as HQNO <jats:italic>O<\/jats:italic>\u2010methyltransferases. The <jats:italic>P.\u00a0aeruginosa<\/jats:italic> exoproducts 4\u2010hydroxyquinolin\u20102(1<jats:italic>H<\/jats:italic>)\u2010one (DHQ), 2\u2010heptylquinolin\u20104(1<jats:italic>H<\/jats:italic>)\u2010one (HHQ), and 2\u2010heptyl\u20103\u2010hydroxyquinolin\u20104(1<jats:italic>H<\/jats:italic>)\u2010one (the \u2018<jats:italic>Pseudomonas<\/jats:italic> quinolone signal\u2019, PQS), some structurally related (iso)quinolones, and the flavonol quercetin were also methylated; however, HQNO was by far the preferred substrate. Both enzymes converted a benzimidazole[1,2\u2010<jats:italic>a<\/jats:italic>]pyridine\u20104\u2010carbonitrile\u2010based compound, representing the scaffold of antimycobacterial substances, to an <jats:italic>N<\/jats:italic>\u2010methylated derivative. We suggest that these promiscuous methyltransferases, newly termed as heterocyclic toxin methyltransferases (Htm), are involved in cellular response to chemical stress and possibly contribute to resistance of mycobacteria toward antimicrobial natural compounds as well as drugs. Thus, synthetic antimycobacterial agents may be designed to be unamenable to methyl transfer.<\/jats:p><\/jats:sec><jats:sec><jats:title>Enzymes<\/jats:title><jats:p><jats:italic>S<\/jats:italic>\u2010adenosyl\u2010<jats:sc>l<\/jats:sc>\u2010methionine:2\u2010heptyl\u20101\u2010hydroxyquinolin\u20104(1<jats:italic>H<\/jats:italic>)\u2010one <jats:italic>O<\/jats:italic>\u2010methyl\u2010transferase, <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/www.qmul.ac.uk\/undergraduate\/coursefinder\/courses\/2020\/chemistry\/\/\">EC\u20092.1.1.\u2010<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1111\/febs.15595","type":"journal-article","created":{"date-parts":[[2020,10,16]],"date-time":"2020-10-16T17:22:21Z","timestamp":1602868941000},"page":"2360-2376","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Modification of the <i>Pseudomonas\u00a0aeruginosa<\/i> toxin 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