Exploiting the porin pathway for polar compound delivery into Gram-negative bacteria.
In Gram-negative bacteria, the outer-membrane represents an additional barrier for antibiotics to permeate inside pathogens. Our inability to come up with novel effective antibiotics mostly relies upon insufficient understanding of the molecular basis behind outer-membrane penetration.



Polar antibiotics can permeate through water-filled porins, such as OmpF and OmpC from Escherichia coli. Through molecular modeling, permeation of imipenem and meropenem was found to be strongly dependent upon capability of drugs to properly align their electric dipole to the internal electric field in the restricted region of the pore. Electrostatics differences between OmpF and OmpC, and modifications along a series of OmpC mutants from E. coli-resistant clinical strains identify a 'preorientation' region, which dramatically affects antibiotic pathway.



A novel perspective is presented, suggesting new molecular properties to be included in drug design.
Department of Biomedical Sciences, University of Cagliari, S.P. 8 km 0.700, I-09042 Monserrato, CA, Italy.
Mariano Andrea
MA
Scorciapino
Department of Physics, University of Cagliari, S.P. 8 km 0.700, I-09042 Monserrato, CA, Italy.
Tommaso
T
D'Agostino
Department of Physics, University of Cagliari, S.P. 8 km 0.700, I-09042 Monserrato, CA, Italy.
Silvia
S
Acosta-Gutierrez
Department of Physics, University of Cagliari, S.P. 8 km 0.700, I-09042 Monserrato, CA, Italy.
Giuliano
G
Malloci
Department of Physics, University of Cagliari, S.P. 8 km 0.700, I-09042 Monserrato, CA, Italy.
Igor
I
Bodrenko
Department of Physics, University of Cagliari, S.P. 8 km 0.700, I-09042 Monserrato, CA, Italy.
Matteo
M
Ceccarelli
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D004926:Escherichia coli / Q000187:drug effects* / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000378:metabolism; D015378:Imipenem / Q000737:chemistry / Q000493:pharmacokinetics; D000077731:Meropenem; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D018272:Porins / Q000737:chemistry / Q000378:metabolism*; D055672:Static Electricity; D013845:Thienamycins / Q000737:chemistry / Q000493:pharmacokinetics
D000900:Anti-Bacterial Agents; D029968:Escherichia coli Proteins; C113724:OmpC protein; C109237:OmpF protein; D018272:Porins; D013845:Thienamycins; D015378:Imipenem; D000077731:Meropenem
antimicrobial drugs; computational chemistry and molecular modelling; drug design