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However, current challenges include rising antibiotic resistance rates and limited efficacy against intracellular pathogens. A novel form of a nanomaterial\u2010based antimicrobial agent is investigated for efficient treatment of an intracellular <jats:italic>Salmonella enterica sv<\/jats:italic> Typhimurium infection. A known antimicrobial polysaccharide, chitosan, is engineered to be readily soluble under neutral aqueous conditions for systemic administration. The modified biologic, named acid\u2010transforming chitosan (ATC), transforms into an insoluble, antimicrobial compound in the mildly acidic intracellular compartment. In cell culture experiments, ATC is confirmed to have antimicrobial activity against intracellular <jats:italic>S<\/jats:italic>. Typhimurium in a concentration\u2010 and pH\u2010dependent manner, without affecting the host cells, RAW264.7 macrophages. For improved cellular uptake and pharmacokinetic\/pharmacodynamic properties, ATC is further complexed with fragment DNA (fDNA), to form nano\u2010sized spherical polyplexes. The resulting ATC\/fDNA polyplexes efficiently eradicated <jats:italic>S<\/jats:italic>. Typhimurium from RAW264.7 macrophages. ATC\/fDNA polyplexes may bind with microbial wall and membrane components. Consistent with this expectation, transposon insertion sequencing of a complex random mutant <jats:italic>S<\/jats:italic>. Typhimurium library incubated with ATC does not reveal specific genomic target regions of the antimicrobial. This study demonstrates the utility of a molecularly engineered nanomaterial as an efficient and safe antimicrobial agent, particularly against an intracellular pathogen.<\/jats:p>","DOI":"10.1002\/mabi.202000408","type":"journal-article","created":{"date-parts":[[2021,4,19]],"date-time":"2021-04-19T04:20:15Z","timestamp":1618806015000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Eradication of Intracellular <i>Salmonella<\/i> Typhimurium by Polyplexes of Acid\u2010Transforming Chitosan and Fragment DNA"],"prefix":"10.1002","volume":"21","author":[{"given":"Julius A.","family":"Edson","sequence":"first","affiliation":[{"name":"Department of Chemical Engineering and Materials Science University of California  Irvine CA 92697 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weiping","family":"Chu","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics 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