Abstract The Type VI Secretion System (T6SS) is a molecular nanomachine that injects toxic effector proteins into the environment or neighboring cells, playing an important role in interbacterial competition and host antagonism during infection. Pseudomonas aeruginosa encodes three T6SSs. One of them, the H1-T6SS, delivers toxins in response to attacks mediated by the T6SS of aggressor bacteria, suggesting that P. aeruginosa can resist T6SS assaults. The mechanisms of resistance are poorly characterized. Here, we perform a CRISPRi screen to identify pathways involved in resistance to T6SS effectors of Acinetobacter baylyi ADP1 and Vibrio cholerae 2740-80. We show that members of the GacA/GacS regulon, such as the mag operon or aas , and GacA-independent factors, like the outer membrane protein OprF, confer resistance to different types of T6SS toxins. Interestingly, some of these T6SS protection mechanisms lead to higher antibiotic susceptibility, suggesting complex evolutionary links between T6SS and antibiotic resistance.
Plack et al. (2025) studied this question.