Acidification May Be Counterproductive For Some Patients With Urinary Tract Infections

MedicalResearch.com Interview with:
Jeffrey P. Henderson, M.D., Ph.D.
Assistant Professor of Medicine and Molecular Microbiology
Center for Women’s Infectious Diseases Research
Division of Infectious Diseases

and Robin Shields-Cutler, Ph.D
Ph.D. Student, Molecular Microbiology and Microbial Pathogenesis
Washington University School of Medicine
St. Louis, Missouri

Medical Research: What is the background for this study?

Response: Increasing antibiotic resistance, together with an appreciation that many patients are particularly susceptible to recurrent Urinary Tract Infections UTIs following antibiotic therapy, motivated interest in the events that occur during early stages of UTI pathogenesis.

Abundant evidence suggests that uropathogenic E.coli must obtain iron from human hosts in order to cause a clinical infection. Early in infection, human cells secrete a protein called siderocalin that is known to limit bacterial growth by sequestering iron. This protein is detectable in the urine of Urinary Tract Infections patients.

Medical Research: What are the main findings?

Response: We obtained urine from a diverse panel of healthy volunteers, inoculated them individually with a uropathogenic E.coli strain, and monitored growth in the presence and absence of a fixed amount of siderocalin. Siderocalin exhibited a remarkably wide range of activity between individuals.

We traced this variation back to differences in urinary pH and to phenolic urinary metabolites. We could significantly facilitate siderocalin’s antibacterial activity in urine by alkalinizing it above 6.5 and adding phenolic metabolites. The metabolites that potentiate siderocalin’s antibacterial effect have been linked to dietary sources such as coffee, tea, and berries. Some of these compounds may further derive from the actions of gut microbes on dietary phenols. The functional basis for these compounds’ properties seems to arise from siderocalin’s ability to use them as molecular grips that chelate iron ions in a form that is difficult for bacteria to access.

From the pathogen perspective, we found that enterobactin, a molecule secreted by E.coli, acts as a microbial countermeasure to urinary siderocalin. Adding a drug-like inhibitor to urine that blocks enterobactin biosynthesis greatly increased siderocalin’s antibacterial effect.

Medical Research: What should clinicians and patients take away from your report?

Response: The results suggest that unappreciated deficiencies in specific dietary phenolic metabolites may contribute to UTI risk and that urinary acidification may be counterproductive in some E.coli urinary tract infections patients.

The work also suggests that non-classical antibiotic strategies based upon cooperation with antibacterial innate immune proteins may be possible for preventing, and possibly treating, urinary tract infections.

Medical Research: What recommendations do you have for future research as a result of this study?

Response: It will be necessary to more carefully identify the urinary metabolites that facilitate siderocalin’s antibacterial activities. It will also be necessary to understand how these metabolites are generated and how they might be delivered to patients. This may take the form of dietary supplements, probiotics, and/or modification of the gut microbiome. Identifying siderophore biosynthesis inhibitors would be an additional, complementary line of investigation. Once candidate approaches are identified, clinical trials aimed at secondary prevention would be a feasible place to start.

Citation:

Robin R. Shields-Cutler, Jan R. Crowley, Chia S. Hung, Ann E. Stapleton, Courtney C. Aldrich, Jonas Marschall, and Jeffrey P. Henderson

Human Urinary Composition Controls Antibacterial Activity of Siderocalin J. Biol. Chem. 2015 290: 15949-15960. First Published on April 10, 2015, doi:10.1074/jbc.M115.645812

 

MedicalResearch.com Interview with:, & Jeffrey P. Henderson, M.D., Ph.D. (2015). Acidification May Be Counterproductive For Some Patients With Urinary Tract Infections