Streptococcus pneumoniae (Spn) colonizes the nasopharynx of children and the elderly but also kills millions worldwide yearly. The secondary bile acid metabolite, deoxycholic acid (DoC), affects the viability of human pathogens but also plays multiple roles in host physiology. We assessed in vitro the antimicrobial activity of DoC and investigated its potential to eradicate Spn colonization using a model of human nasopharyngeal colonization and an in vivo mouse model of colonization. At a physiological concentration DoC (0.5 mg/ml; 1.27 mM) killed all tested Spn strains (N=48) two hours post-inoculation. The model of nasopharyngeal colonization showed that DoC eradicated colonization by Spn strains as soon as 10 min post-exposure. The mechanism of action did not involve activation of autolysis since the autolysis-defective double mutants Δ lytA Δ lytC and ΔspxBΔlctO were as susceptible to DoC as was the wild-type (WT). Oral streptococcal species (N=20), however, were not susceptible to DoC (0.5 mg/ml). Unlike trimethoprim, whose spontaneous resistance frequency (srF) for TIGR4 or EF3030 was ≥1x10 −9 , no spontaneous resistance was observed with DoC (srF≥1x10- 12 ). Finally, the efficacy of DoC to eradicate Spn colonization was assessed in vivo using a topical route via intranasal (i.n.) administration and as a prophylactic treatment. Mice challenged with Spn EF3030 carried a median of 4.05x10 5 cfu/ml four days post-inoculation compared to 6.67x10 4 cfu/ml for mice treated with DoC. Mice in the prophylactic group had a ∼99% reduction of the pneumococcal density (median, 2.61 x10 3 cfu/ml). Thus, DoC, an endogenous human bile salt, has therapeutic potential against Spn.
Streptococcus pneumoniae (pneumococcus) colonizes the upper respiratory tract, including the nasopharynx, of children and the elderly. Despite antibiotics and vaccines readily available, pneumococcus kills millions worldwide yearly. We have found that the secondary bile acid metabolite and endogenous salt deoxycholic acid (DoC) affects the viability of this human pathogen while also playing multiple roles in host physiology. Via in vitro studies, we assessed the anti-microbial activity of DoC and investigated its potential to eradicate S. pneumoniae colonization using a model of human nasopharyngeal colonization and an in vivo mouse model. At a physiological concentration, DoC (0.5 mg/ml; 1.27 mM) killed all tested strains of S. pneumoniae (n=48) 2 hours post-inoculation. Our model of nasopharyngeal colonization showed that DoC eradicated colonization by S. pneumoniae strains as quickly as 10 minutes post-exposure. The mechanism of action did not involve activating autolysis since autolysis-defective double mutant strains (Δ lytAΔ lytC and Δ spxBΔ lctO) were found to be as susceptible to DoC as the wild-type strain (WT). Oral streptococcal species (n=20) were, however, not as susceptible to DoC at 0.5 mg/ml. Unlike trimethoprim, whose spontaneous resistance frequency (srF) for TIGR4 or EF3030 was ≥ 1 x 10-9, no spontaneous resistance was observed with DoC. Finally, the efficacy of DoC to eradicate S. pneumoniae colonization was assessed in vivo using an intranasal topical route (i.n.) and separately as prophylactic treatment. Mice that were challenged with S. pneumoniae EF3030 carried a median of 4.05 x 105 CFU/ml four days post-inoculation compared to 6.67 x 104 CFU/ml for mice treated with DoC. Furthermore, mice in the prophylactic DoC group had approximately a 99% reduction of pneumococcal density illustrating the possibility of deoxycholic acid as a safe, endogenous human bile salt with therapeutic potential against increasingly-resistant S. pneumoniae strains. This study was in part supported by grants from the National Institutes of Health (NIH; 1R21AI144571-01 and 1R21AI151571-01A1 to J.E.V.). B.A. was supported by a Fulbright scholarship awarded by the U.S. Department of State. The content is solely the responsibility of the authors and does not necessarily represent the official view of the NIH or the U.S. Department of State. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Streptococcus pneumoniae (Spn) colonizes the nasopharynx of children and the elderly but also kills millions worldwide yearly. The secondary bile acid metabolite, deoxycholic acid (DoC), affects the viability of human pathogens but also plays multiple roles in host physiology. We assessed in vitro the antimicrobial activity of DoC and investigated its potential to eradicate Spn colonization using an ex vivo model of human nasopharyngeal colonization and an in vivo mouse model of colonization. At a physiological concentration DoC (0.5 mg/ml; 1.27 mM) killed all tested Spn strains (N=48) two h post-inoculation. The ex-vivo model of nasopharyngeal colonization showed that DoC eradicated colonization by Spn strains as soon as 10 min post-exposure. The mechanism of action did not involve activation of autolysis since the autolysis-defective double mutants ΔlytAΔlytC and ΔspxBΔlctO were as susceptible to DoC as was the wild-type (WT). Oral streptococcal species (N=20), however, were not susceptible to DoC (0.5 mg/ml). Unlike trimethoprim, whose spontaneous resistance frequency (srF) for TIGR4 or EF3030 was ≥1x10-9, no spontaneous resistance was observed with DoC (srF≥1x10-12). Finally, the efficacy of DoC to eradicate Spn colonization was assessed in vivo using a topical route via intranasal (i.n.) administration and as a prophylactic treatment. Mice challenged with Spn EF3030 carried a median of 4.05x105 cfu/ml four days post-inoculation compared to 6.67x104 cfu/ml for mice treated with DoC. Mice in the prophylactic group had a ~99% reduction of the pneumococcal density (median, 2.61 x103 cfu/ml). Thus, DoC, an endogenous human bile salt, has therapeutic potential against Spn.
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