Pseudomonas aeruginosa is a Gram-negative bacterium that causes dangerous hospital-acquired infections and has developed antibiotic resistance. Hence, a considerable research effort has been directed towards fighting this organism. Most antibiotics require to cross the outer membrane (OM) in order to reach their targets and accomplish their function, and this step often compromises their efficacy. Therefore, understanding the molecular transport mechanism through the OM is crucial in antibacterial drug discovery. The main gate for small molecules to pass through the OM are porins, membrane proteins that exhibit a β-barrel folding. Here we decipher the transport mechanism of glucose across OprB, a sugar-specific porin from Pseudomonads, by means of molecular dynamics in conjunction with metadynamics. Our results show that residues located in the constriction region of the pore play a major role in the transport, screening both the charge and the size of molecules (i.e., positive/neutral monosaccharides). With this in mind, we also elucidate the transport mechanism of 2-acetamido-1,2-dideoxynojirimycin (DNJ-NAc) though OprB, since is an anti-infective monosaccharide positively charged and structurally similar to glucose. Thus, we exemplify how to exploit the transport though specific porins following the so-called Trojan Horse strategy.
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