Figure 3.

The adaptability of MBLs to different bacterial hosts depends on the impact of protein expression on biological fitness. This model describes the adaptability of MBLs to different bacterial hosts based on the processing of their SPs (39). An MBL is confined to a narrow range of bacteria (left panel) when its expression in nonfrequent hosts causes the accumulation of toxic precursor forms (shown as green misfolded protein) in the periplasmic face of the inner membrane because of an inefficient translocation and processing that compromises the bacterial growth (bottom left panel). This toxicity correlates with an increase in the production of outer membrane vesicles (OMVs) that incorporate both the mature (folded protein) and the precursor protein (misfolded) to alleviate the envelope stress; thus acting as a vesicle-mediated detoxification mechanism. By contrast, a broad host MBL (right panel) is produced by different bacteria without fitness cost (bottom right panel). These MBLs are efficiently translocated and processed. In these cases, the level of selective packaging into OMVs depends on the interaction of the MBL with the outer membrane, either by membrane anchoring (violet folded protein) or by specific electrostatic interactions (cyan folded protein) through a positively charged patch. The double-headed dashed arrow represents the binding equilibrium of soluble periplasmic MBL with the outer membrane, which favors protein packaging into OMVs. EV, cells carrying the empty vector; MBL, metallo-β-lactamase; SP, signal peptide.