IscR-mediated morphological regulation confers virulence and stress resistance by reducing stress molecule uptake in Acinetobacter baumannii

Living organisms must adequately respond to stress to survive and proliferate. Bacterial pathogens face multiple stressors during infections, including oxidative stress from host innate immune cells and antibiotic treatment from clinical therapy. The pathogenic bacterium Acinetobacter baumannii is considered the most critical threat to public health due to its broad antibiotic resistance. However, it is poorly known how A. baumannii properly responds to antibiotics and stress molecules during infection. Here, we investigate the mechanisms by which A. baumannii regulates its morphology to reduce the uptake of stress molecules under oxidative stress and antibiotic exposure, thereby conferring virulence and survival during infection. The transcriptional regulator IscR responds to oxidative stress by upregulating pbp1a , which encodes an enzyme involved in peptidoglycan biosynthesis. Under oxidative stress, bacteria undergo a morphological shift from a rod to a coccoid form, reducing their surface area and thus decreasing their absorption of reactive oxygen species. Inactivation of either iscR or pbp1a results in an elongated morphology characterized by an elevated surface area, thereby reducing A. baumannii survival under oxidative stress. Furthermore, IscR-mediated morphological control is essential for survival under antibiotic treatment. Moreover, IscR-mediated morphology regulation is required for A. baumannii survival in macrophage and mouse models. These findings elucidate a strategy by which A. baumannii uses IscR to adapt to stress through morphological control, facilitating its survival during infections against both immune response and antibiotic therapy.