Overcoming reduced antibiotic susceptibility in intracellular Salmonella enterica serovar Typhimurium using AR-12.
M Shamim Hasan ZahidDevika M VarmaMonica M JohnsonAntonio LandavazoEric M BachelderBruce E BloughKathryn M MoorePublished in: FEMS microbiology letters (2021)
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.
Keyphrases
- drug resistant
- reactive oxygen species
- listeria monocytogenes
- multidrug resistant
- randomized controlled trial
- cell proliferation
- emergency department
- single cell
- stem cells
- endoplasmic reticulum stress
- clinical trial
- open label
- gram negative
- newly diagnosed
- protein kinase
- study protocol
- antimicrobial resistance
- double blind