Interplay between porin deficiency, fitness, and virulence in carbapenem-non-susceptible Pseudomonas aeruginosa and Enterobacteriaceae.

Abstract

The increasing resistance of Gram-negative bacteria to last resort antibiotics, such as carbapenems, is particularly of concern as it is a significant cause of global health threat. In this context, there is an urgent need for better understanding underlying mechanisms leading to antimicrobial resistance in order to limit its diffusion and develop new therapeutic strategies. In this review, we focus on the specific role of porins in carbapenem-resistance in Enterobacteriaceae and Pseudomonas aeruginosa, which are major human pathogens. Porins are outer membrane proteins, which play a key role in the bacterial permeability to allow nutrients to enter and toxic waste to leave. However, these channels are also "Achilles' heel" of bacteria as antibiotics can also pass through them to reach their target and kill the bacteria. After describing normal structures and pathways regulating the expression of porins, we discuss strategies implemented by bacteria to limit the access of carbapenems to their cytoplasmic target. We further examine the real impact of changes in porins on carbapenems susceptibility. Finally, we decipher what is the effect of such changes on bacterial fitness and virulence. Our goal is to integrate all these findings to give a global overview of how bacteria modify their porins to face antibiotic selective pressure trying to not induce fitness cost.