Fig 4. Model.

(A) Host RNS intoxicate the TCA cycle of persisters, thereby limiting their cellular respiration while residing within host cells. Consequently, intramacrophage persisters intoxicated with RNS remain in a growth-arrested state but are unable to sustain efficient efflux activity. (B) Intramacrophage population of Salmonella displays strong phenotypic heterogeneity. In absence of antibiotics, most bacteria are actively growing (gray) whereas a subpopulation of cells remains in a non-growing state (brown). Treatment with cefotaxime (cef) results in the killing of the growing population but is ineffective against non-growers. In contrast, ciprofloxacin eliminates not only the growing population but also non-growers that are unable to maintain an efficient efflux activity. Since RNS-dependent persisters cannot sustain such activity, they are unable to withstand ciprofloxacin exposure during infection.