Abstract
Background:
Many clinically relevant bacterial pathogens are encapsulated, as exemplified by Salmonella enterica serovar Typhi. S. Typhi, the causative agent of the life-threatening systemic disease typhoid fever, expresses Vi as the outermost surface glycan that protects the bacteria from host immune responses. Drug resistant S. Typhi strains and Vi variants are spread globally.
Methods:
Whole genome sequences (WGS) of 24,206 S. Typhi clinical isolates were analysed for genetic traits for antibiotic resistance. Rifampin treated S. Typhi was characterised at the molecular and cellular level. The effects of rifampin mediated decapsulation on bacterial clearance were studied using human primary neutrophils and mouse infection models. Computational and functional studies on other encapsulated bacteria were also carried out.
Findings:
Our WGS analyses indicate that almost all S. Typhi clinical isolates are susceptible to rifamycins and azithromycin. Rifampin at sub-minimum inhibitory concentration (MIC) levels, which is naturally established in patients during treatment, eliminates the protective capsule Vi, a process referred to as 'decapsulation', thereby enhancing bacterial clearance. Antibiotic-mediated decapsulation of S. Typhi appears specific to rifamycins, since azithromycin does not decapsulate S. Typhi. Rifampin mediated decapsulation occurs at the transcriptional level, where both high AT content and specific RpoB residues play a crucial role. Rifampin also effectively decapsulates Vi variants, which accounts for 1 in 5 S. Typhi isolates at the global level. A mechanistic explanation for rifampin mediated decapsulation of S. Typhi appears to be applicable to other encapsulated pathogens, including S. Paratyphi C.
Interpretation:
Nearly all S. Typhi isolates are susceptible to rifampin. This study reveals a new mechanism of rifamycin actions; rifampin enhances bacterial clearance by inhibiting the expression of the protective capsular polysaccharides and other key virulence factors. This study has important implications for treating drug resistant S. Typhi, Vi capsule variants, and other encapsulated bacterial pathogens.
Funding:
National Institute of Allergy and Infectious Diseases.