Fig. 10: Model describing the putative mode of action of NV716 as an adjuvant molecule capable of potentiating antibiotic activity and of exerting anti-virulence effects at sub-MIC concentrations.
(1) Potentiator of antibiotic activity: At subMIC concentration, NV716 interacts with LPS and increases the permeability of the outer membrane of P. aeruginosa, while at the same time inhibiting the activity of efflux transporters by an unknown mechanism13, which facilitates the penetration of antibiotics. At its MIC, it also permeabilizes the inner membrane of the bacteria, leading to their death without gross alteration of the bacterial morphological integrity. (2) Anti-virulence compound: It also reduces the expression of quorum sensing-related genes, causing a downregulation of virulence factors like rhamnolipids, pyocyanin, elastase, and of T6SS-related genes, as well as a subsequent reduction in motility and biofilm formation. The chemical structure of NV716 is also shown, with the aminated functions (protonable at physiological pH) circled in blue.
