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Since LT inhibitor development is underexplored, we probed 15 N\u2010acetyl\u2010containing heterocycles in a structure\u2010guided fashion for their ability to inhibit and bind to the <jats:italic>Campylobacter jejuni<\/jats:italic> LT Cj0843c. Ten GlcNAc analogs were synthesized with substitutions at the C1 position, with two having an additional modification at the C4 or C6 position. Most of the compounds showed weak inhibition of Cj0843c activity. Compounds with alterations at the C4 position, replacing the \u2010OH with a \u2010NH<jats:sub>2<\/jats:sub>, and C6 position, the addition of a \u2010CH<jats:sub>3<\/jats:sub>, yielded improved inhibitory efficacy. All 10 GlcNAc analogs were crystallographically analyzed via soaking experiments using Cj0843c crystals and found to bind to the +1 +2 saccharide subsites with one of them additionally binding to the \u22122 \u22121 subsite region. We also probed other N\u2010acetyl\u2010containing heterocycles and found that sialidase inhibitors N\u2010acetyl\u20102,3\u2010dehydro\u20102\u2010deoxyneuraminic acid and siastatin B inhibited Cj0843c weakly and crystallographically bound to the \u22122 \u22121 subsites. Analogs of the former also showed inhibition and crystallographic binding and included zanamivir amine. This latter set of heterocycles positioned their N\u2010acetyl group in the \u22122 subsite with additional moieties interacting in the \u22121 subsite. Overall, these results could provide novel opportunities for LT inhibition via exploring different subsites and novel scaffolds. The results also increased our mechanistic understanding of Cj0843c regarding peptidoglycan GlcNAc subsite binding preferences and ligand\u2010dependent modulation of the protonation state of the catalytic E390.<\/jats:p>","DOI":"10.1002\/pro.4683","type":"journal-article","created":{"date-parts":[[2023,5,20]],"date-time":"2023-05-20T14:33:25Z","timestamp":1684593205000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Exploring the inhibition of the soluble lytic transglycosylase Cj0843c of <i>Campylobacter jejuni<\/i> via targeting different sites with different scaffolds"],"prefix":"10.1002","volume":"32","author":[{"given":"Vijay","family":"Kumar","sequence":"first","affiliation":[{"name":"Department of Biochemistry Case Western Reserve University  Cleveland Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacob","family":"Boorman","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Case Western Reserve University  Cleveland Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William J.","family":"Greenlee","sequence":"additional","affiliation":[{"name":"MedChem Discovery Consulting, LLC  Teaneck New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ximin","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Animal Science University of Tennessee  Knoxville Tennessee USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Animal Science University of Tennessee  Knoxville Tennessee USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Focco","family":"van den Akker","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Case Western Reserve University  Cleveland Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,6,16]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444909052925"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1089\/mdr.2011.0231"},{"key":"e_1_2_6_4_1","doi-asserted-by":"crossref","unstructured":"BowersKJ ChowE XuH DrorRO EastwoodMP GregersenBA et al.Scalable algorithms for molecular dynamics simulations on commodity clusters. 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