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Enzymes of the branched\u2010chain amino acid (BCAA) biosynthesis pathway are an attractive target for novel anti\u2010microbial drug development. Dihydroxy\u2010acid dehydratase (DHAD) is the third enzyme in the BCAA biosynthesis pathway. It relies on an Fe\u2212S cluster for catalytic activity and has recently also gained attention as a catalyst in cell\u2010free enzyme cascades. Two types of Fe\u2212S clusters have been identified in DHADs, i.e. [2Fe\u22122S] and [4Fe\u22124S], with the latter being more prone to degradation in the presence of oxygen. Here, we characterise two DHADs from bacterial human pathogens, <jats:italic>Staphylococcus aureus<\/jats:italic> and <jats:italic>Campylobacter jejuni<\/jats:italic> (<jats:italic>Sa<\/jats:italic>DHAD and <jats:italic>Cj<\/jats:italic>DHAD). Purified <jats:italic>Sa<\/jats:italic>DHAD and <jats:italic>Cj<\/jats:italic>DHAD are virtually inactive, but activity could be reversibly reconstituted in vitro (up to \u223c19,000\u2010fold increase with <jats:italic>k<jats:sub>cat<\/jats:sub><\/jats:italic> as high as \u223c6.7\u2005s<jats:sup>\u22121<\/jats:sup>). Inductively\u2010coupled plasma\u2010optical emission spectroscopy (ICP\u2010OES) measurements are consistent with the presence of [4Fe\u22124S] clusters in both enzymes. N\u2010isopropyloxalyl hydroxamate (IpOHA) and aspterric acid are both potent inhibitors for both <jats:italic>Sa<\/jats:italic>DHAD (<jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub>=7.8 and 51.6\u2005\u03bcM, respectively) and <jats:italic>Cj<\/jats:italic>DHAD (<jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub>=32.9 and 35.1\u2005\u03bcM, respectively). These compounds thus present suitable starting points for the development of novel anti\u2010microbial chemotherapeutics.<\/jats:p>","DOI":"10.1002\/chem.202200927","type":"journal-article","created":{"date-parts":[[2022,5,10]],"date-time":"2022-05-10T06:29:01Z","timestamp":1652164141000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Dihydroxy\u2010Acid Dehydratases From Pathogenic Bacteria: Emerging Drug Targets to Combat Antibiotic Resistance"],"prefix":"10.1002","volume":"28","author":[{"given":"Tenuun","family":"Bayaraa","sequence":"first","affiliation":[{"name":"School of Chemistry and Molecular Biosciences The University of Queensland  Brisbane 4072 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose","family":"Gaete","sequence":"additional","affiliation":[{"name":"School of Chemistry and Molecular Biosciences The University of Queensland  Brisbane 4072 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