Prophylactic Inhibition of Colonization by Streptococcus pneumoniae with the Secondary Bile Acid Metabolite Deoxycholic Acid

• Published in: Infection and immunity Vol. 89; no. 12; p. e0046321
• Main Authors: Vidal, Jorge E., Wier, Meagan N., A. Angulo-Zamudio, Uriel, McDevitt, Erin, Jop Vidal, Ana G., Alibayov, Babek, Scasny, Anna, Wong, Sandy M., Akerley, Brian J., McDaniel, Larry S.
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 16.11.2021
• Subjects: Animals; Bacterial Infections; Bacteriology; Bile Acids and Salts - metabolism; Deoxycholic Acid - metabolism; Deoxycholic Acid - pharmacology; Disease Models, Animal; Disease Susceptibility; Drug Resistance, Bacterial; Host-Pathogen Interactions; Humans; Mice; Mutation; N-Acetylmuramoyl-L-alanine Amidase - genetics; Nasopharynx - microbiology; Pneumococcal Infections - metabolism; Pneumococcal Infections - microbiology; Pneumococcal Infections - prevention & control; Streptococcus pneumoniae - drug effects; Streptococcus pneumoniae - genetics; Streptococcus pneumoniae - growth & development; deoxycholate; bile acids; colonization; eradication; Streptococcus pneumoniae
• ISSN: 0019-9567; 1098-5522; 1098-5522
• DOI: 10.1128/IAI.00463-21

Streptococcus pneumoniae 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. Streptococcus pneumoniae 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 S. pneumoniae 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 S. pneumoniae strains ( n  = 48) 2 h postinoculation. The model of nasopharyngeal colonization showed that DoC eradicated colonization by S. pneumoniae strains as soon as 10 min postexposure. The mechanism of action did not involve activation of autolysis, since the autolysis-defective double mutants Δ lytA Δ lytC and Δ spxB Δ lctO 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 ≥1 × 10 −9 , no spontaneous resistance was observed with DoC (srF, ≥1 × 10 –12 ). Finally, the efficacy of DoC to eradicate S. pneumoniae colonization was assessed in vivo using a topical route via intranasal (i.n.) administration and as a prophylactic treatment. Mice challenged with S. pneumoniae EF3030 carried a median of 4.05 × 10 5 CFU/ml 4 days postinoculation compared to 6.67 × 10 4 CFU/ml for mice treated with DoC. Mice in the prophylactic group had an ∼99% reduction of the pneumococcal density (median, 2.61 × 10 3 CFU/ml). Thus, DoC, an endogenous human bile salt, has therapeutic potential against S. pneumoniae .