Exposure to third generation cephalosporin induces L-form transition in Shigella sonnei, potentially acting as a bacterial reservoir for persistent infection

Shigellosis is a major global health threat with a significant Disability Adjusted Life years (DALY) burden, particularly in India, where rising multidrug-resistance (MDR) compromises therapies. Bacteria may survive antibiotics by transitioning into cell wall-deficient L-forms, which are intrinsically resistant to {beta}-lactams and can revert to a virulent state, potentially causing relapsing infections. Here we characterized a clinical MDR isolate Shigella sonnei HK8, a.k.a. PD552A, whose genome contains key resistance (gyrA, PBP3) and virulence (icsA) genes. Exposure to ceftriaxone induced a transition into a viable L-form state that was hyper-adhesive to macrophages in vitro. However, this survival adaptation was linked to a profound loss of pathogenicity. Using murine and guinea pig models, the L-form variant was shown to be completely attenuated, failing to cause the keratoconjunctivitis, diarrheal disease, or significant histopathology characteristic of the wild-type strain. These findings reveal a critical virulence-survival trade-off, positioning the L-form as a \"stealth\" phenotype that enables bacterial persistence at the expense of acute virulence. This offers a potential mechanism for asymptomatic carriage and recurrent infections, highlighting a significant challenge in the management of shigellosis.