biostudies-literatureZahid MSHNIAID NIH HHSNational Institutes of Healthfnab062https://www.ebi.ac.uk/biostudies/studies/S-EPMC8433491biostudies-literatureUnknown368(11)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 FEMS microbiology lettersOvercoming reduced antibiotic susceptibility in intracellular Salmonella enterica serovar Typhimurium using AR-12.PMC8433491R01AI125147R01 AI125147Ainslie KMJohnson MMZahid MSHVarma DMLandavazo ABachelder EMBlough BEfalseOvercoming reduced antibiotic susceptibility in intracellular Salmonella enterica serovar Typhimurium using AR-12.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 2021-01-01T00:00:00Z2021 Jun2025-04-19T18:18:57.025Z2025-04-19T18:18:57.025ZS-EPMC84334913408931510.1093/femsle/fnab062