Tissue compartmentalization enables Salmonella persistence during chemotherapy

Abstract

Antimicrobial chemotherapy can fail to eradicate the pathogen, even in the absence of antimicrobial resistance. Persisting pathogens can subsequently cause relapsing diseases. In vitro studies suggest various mechanisms of antibiotic persistence, but their in vivo relevance remains unclear because of the difficulty of studying scarce pathogen survivors in complex host tissues. Here, we localized and characterized rare surviving Salmonella in mouse spleen using high-resolution whole-organ tomography. Chemotherapy cleared >99.5% of the Salmonella but was inefficient against a small Salmonella subset in the white pulp. Previous models could not explain these findings: drug exposure was adequate, Salmonella continued to replicate, and host stresses induced only limited Salmonella drug tolerance. Instead, antimicrobial clearance required support of Salmonella-killing neutrophils and monocytes, and the density of such cells was lower in the white pulp than in other spleen compartments containing higher Salmonella loads. Neutrophil densities declined further during treatment in response to receding Salmonella loads, resulting in insufficient support for Salmonella clearance from the white pulp and eradication failure. However, adjunctive therapies sustaining inflammatory support enabled effective clearance. These results identify uneven Salmonella tissue colonization and spatiotemporal inflammation dynamics as main causes of Salmonella persistence and establish a powerful approach to investigate scarce but impactful pathogen subsets in complex host environments.

Antibiotic persistence of Brucella abortus in its protective intracellular niche

“…Other drugs, such as Tridecaptin M, which sensitizes Acinetobacter baumanii persisters for killing by rifampicin [124] or 4-hexylresorcinol (4-HR), a phenolic lipid, which potentiated the MIC of various classes of antibiotics up to 50-fold for different bacterial species such as Klebsiella pneumoniae , S. aureus and P. aeruginosa [125] demonstrate that persisters can specifically be targeted. Another mechanism to improve the treatment of relapsing infections was demonstrated recently for Salmonella by Li, Claudi, Fanous et al [126]. They showed that eradication of Salmonella from infected host tissue in a mouse model of infection was only possible after addition of adjunctive immune therapy, highlighting the relevance of the immune system in eradication of persistent infections.…”

Salmonella enterica Infections Are Disrupted by Two Small Molecules That Accumulate within Phagosomes and Differentially Damage Bacterial Inner Membranes

“…Despite these advantages, current lipophilic antibiotic therapies are imperfect at treating intracellular infections. Although lipophilic antibiotics penetrate and accumulate in cells, they are not always efficacious ( 89 , 94 ) and instead depend on the physicochemical microenvironment of the infection and synergy with host defenses ( 88 , 95 , 96 ). Moreover, lipophilic antibiotics typically target actively growing intracellular bacteria in lieu of nongrowing or persister cell types that require a minimum level of active PMF and ATP metabolism ( 97 – 100 ).…”

Antibiotic persistence of intracellular Brucella abortus

“…Other drugs, such as Tridecaptin M, which sensitizes Acinetobacter baumanii persisters for killing by rifampicin [122] or 4-hexylresorcinol (4-HR), a phenolic lipid, which potentiated the MIC of various classes of antibiotics up to 50-fold for different bacterial species such as Klebsiella pneumoniae, S. aureus and P. aeruginosa [123] demonstrate that persisters can specifically be targeted. Another mechanism to improve the treatment of relapsing infections was demonstrated recently for Salmonella by Li, Claudi, Fanous et al [124]. They showed that eradication of Salmonella from infected host tissue in a mouse model of infection was only possible after addition of adjunctive immune therapy, highlighting the relevance of the immune system in eradication of persistent infections.…”