The Sweet Gateway of Pseudomonads: Sugar Transport Across the OprB Porin

Session: 
PS2 Poster session 2 Even numbers
Code: 
P42
Location (hall): 
Foyer
Start/end time: 
Tuesday, July 2, 2019 - 15:45 to 17:15
Joan
Coines

Joan Coines1, Silvia Acosta-Gutiérrez2, Igor Bodrenko2, Carme Rovira1,3, Matteo Ceccarelli2

1Departament de Química Inorgànica i Orgànica and Institut de Química Teòrica i Computacional (IQTCUB), Universitat de Barcelona, Martí i Franquès 1, 08028, Barcelona, Spain, 2Department of Physics, University of Cagliari, Cittadella Universitaria, S.P.8-km 0.700, 09042 Monserrato, Cagliari, Italy, 3Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluís Companys 23, 08018, Barcelona, Spain

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.[1] 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.[2] 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).[3] With this in mind, we also elucidate the transport mechanism of 2-acetamido-1,2-dideoxynojirimycin (DNJ-NAc)[4] 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.

Transport mechanism of glucose and DNJ-NAc (natural substrate and an antibiotic, respectively) through the sugar-specific porin OprB from pseudomonads.

References: 
  1. Wagner, S. et al. Novel Strategies for the Treatment of Pseudomonas aeruginosa Infections. J. Med. Chem. 2016, 59, 5929–5969.
  2. Brown, D. G., May-Dracka, T. L., Gagnon, M. M. & Tommasi, R. Trends and exceptions of physical properties on antibacterial activity for gram-positive and gram-negative pathogens. J. Med. Chem. 2014, 57, 10144–10161.
  3. Coines, J., Acosta-Gutierrez, S., Bodrenko, I., Rovira, C. & Ceccarelli, M. Glucose transport via the pseudomonad porin OprB: implications for the design of Trojan Horse anti-infectives. Phys. Chem. Chem. Phys. 2019, 21, 8457–8463.
  4. Yamaguchi, T. et al. Inhibitors for bacterial cell-wall recycling. ACS Med. Chem. Lett. 2012, 3, 238–242.

Sponsors

Sponsors