A dual-therapy approach for the treatment of biofilm-mediated Salmonella gallbladder carriage.

Jenna L Sandala,Mark M Hahn,Katherine Woolard,Bradley W Eichar,Christian Melander,Laura G Kuo,William M Huggins,John S Gunn,Akash K Basak,Andreas J Baumler

doi:10.1371/journal.ppat.1009192

Abstract

Asymptomatic carriage of Salmonella Typhi continues to facilitate the transmission of typhoid fever, resulting in 14 million new infections and 136,000 fatalities each year. Asymptomatic chronic carriage of S. Typhi is facilitated by the formation of biofilms on gallstones that protect the bacteria from environmental insults and immune system clearance. Here, we identified two unique small molecules capable of both inhibiting Salmonella biofilm growth and disrupting pre-formed biofilm structures without affecting bacterial viability. In a mouse model of chronic gallbladder Salmonella carriage, treatment with either compound reduced bacterial burden in the gallbladder by 1–2 logs resulting in bacterial dissemination to peripheral organs that was associated with increased mortality. Co-administration of either compound with ciprofloxacin not only enhanced compound efficacy in the gallbladder by a further 1–1.5 logs for a total of 3–4.5 log reduction, but also prevented bacterial dissemination to peripheral organs. These data suggest a dual-therapy approach targeting both biofilm and planktonic populations can be further developed as a safe and efficient treatment of biofilm-mediated chronic S. Typhi infections.

Highlights

Typhoid fever is an infectious disease caused by Salmonella Typhi
Typhi), a bacterium that causes as many as 14 million new infections and 136,000 deaths annually
The compound JG-1 was initially identified by screening a library of 4,000 small molecules each at 5 μM purchased from ChemBridge (San Diego, CA)

Summary

Introduction

Typhi) is the etiological agent of typhoid fever, an acute systemic infection that is characterized by fever, malaise, and abdominal pain. Typhoid fever is rarely reported in more developed countries such as the United States; the disease remains endemic in a number of developing regions where sanitation is relatively poor, resulting in 14 million new infections and 136,000 deaths each year [4]. Typhi after symptoms have subsided [3,5,6]. Such asymptomatic chronic carriage presents a major public health problem in endemic regions, as carriers unknowingly serve as a reservoir for typhoidal serovars and remain capable of spreading the disease via fecal contamination [3]. Typhi infections are primarily localized to the gallbladder and are facilitated by the formation of biofilms on cholesterol gallstones [3,6,7,8,9]

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Conclusion