{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T06:17:19Z","timestamp":1772777839802,"version":"3.50.1"},"reference-count":51,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T00:00:00Z","timestamp":1622505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI125147"],"award-info":[{"award-number":["R01AI125147"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,6,16]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Host-directed therapies (HDTs) could enhance the activity of traditional antibiotics. AR-12 is a promising HDT against intracellular pathogens including Salmonella enterica serovar Typhimurium, and has been shown to act through modulation of autophagy and the Akt kinase pathway. Since AR-12 does not inhibit the growth of planktonic bacteria but only works in conjunction with the infected host-cell, we hypothesized that AR-12 could enhance the activity of antibiotics in less-susceptible strains in the intracellular host environment. We found that repetitive passaging of S. typhimurium in macrophages in the absence of antibiotics led to a 4-fold reduction in their intracellular susceptibility to streptomycin (STR), but had no effect on the bacteria's sensitivity to AR-12. Moreover, when the host-passaged strains were treated with a combined therapy of AR-12 and STR, there was a significant reduction of intracellular bacterial burden compared to STR monotherapy. Additionally, co-treatment of macrophages infected with multi-drug resistant S. typhimurium with AR-12 and STR or ampicillin showed enhanced clearance of the intracellular bacteria. The drug combination did not elicit this effect on planktonic bacteria. Overall, AR-12 enhanced the clearance of less susceptible S. typhimurium in an intracellular environment.<\/jats:p>","DOI":"10.1093\/femsle\/fnab062","type":"journal-article","created":{"date-parts":[[2021,6,3]],"date-time":"2021-06-03T03:14:48Z","timestamp":1622690088000},"source":"Crossref","is-referenced-by-count":5,"title":["Overcoming reduced antibiotic susceptibility in intracellular<i>Salmonella enterica<\/i>serovar Typhimurium using AR-12"],"prefix":"10.1093","volume":"368","author":[{"given":"M Shamim Hasan","family":"Zahid","sequence":"first","affiliation":[{"name":"Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Devika M","family":"Varma","sequence":"additional","affiliation":[{"name":"Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North 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